Oral end tidal carbon dioxide probe for diagnosing pulmonary arterial hypertension

ABSTRACT

This disclosure concerns improved capabilities for evaluating pulmonary arterial hypertension (PAH). A system and method of evaluating PAH in a subject may include measuring end tidal partial pressure of exhaled carbon dioxide in the subject, wherein the measurement is made orally using described systems or devices. Integrated sensors enable the measurement and characterization of other respiratory gas components, some of which may be indicative of disease. The system and method can be used to monitor a course of treatment for PAH.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application Ser. No.61/476,133, filed Apr. 15, 2011, the entire disclosure of which isherein incorporated by reference.

This application is a continuation-in-part of the following U.S. patentapplications, each of which is incorporated by reference in itsentirety: U.S. patent application Ser. No. 12/578,841, filed Oct. 14,2009, which claims the benefit of U.S. patent application Ser. No.61/106,066, filed Oct. 16, 2008, the entire disclosure of which isherein incorporated by reference.

BACKGROUND

Field:

The present invention relates to an oral end tidal carbon dioxide probe.

Description of the Related Art:

Pulmonary embolism (PE) remains a diagnostic challenge and many studiesare performed with a low yield at substantial financial cost andpotential risk from radiation. End tidal carbon dioxide (EtCO₂) is asurrogate for pulmonary vascular obstruction and subsequent dead spaceventilation. Using EtCO₂ as an initial screening test in patients beingevaluated for PE would potentially spare many unnecessary, low-yielddiagnostic studies and their associated risk and financial burden.

Pulmonary embolism (PE) is a common concern in the evaluation of diverseclinical presentations including chest pain, dyspnea and hypoxemia.Extensive diagnostic evaluation, including contrast enhanced helicalcomputed tomography (CT), is frequently undertaken, despite a relativelylow incidence of disease [2]. In addition to the cost of these studies,the risks of contrast and radiation exposure add to the burden ofevaluation [3, 4]. Throughout this Specification, the numeral(s) insideof brackets refers to a literature citation. The list of literaturecited appears at the end of the Detailed Description.

Diagnostic algorithms to simplify testing procedures in PE diagnosishave been explored, most combining D-dimer testing and CT angiography[5, 6]. D-dimer testing requires venipuncture and time for testperformance. [1, 5] CT angiography use in PE diagnosis has increasedmarkedly [2]. As a low percentage of CT angiograms demonstrate PE [2, 7,8], concern has been raised of the contrast and radiation risk [4, 9].Clinical prediction rules, including the Wells score, have also beenproposed [6, 10] which have the advantage of instantaneous results,avoidance of invasive procedures, and low risk and cost.

With rising numbers of patients being evaluated for PH and thesubstantial cost, time, and potential risk in evaluation of pulmonaryvascular disease [48], there is an interest in developing new,non-invasive diagnostic techniques to identify patients at low risk forPAH. Currently, final confirmation of diagnosis of PAH requires RHC, inpart, to rule out PVH. While there are clinical and echocardiographicfeatures that may make PVH more likely [31, 43], these indicators areoften not adequately compelling to dissuade clinicians from pursuing RHCin patients with elevated right ventricular systolic pressure onechocardiography or evidence of cor pulmonale. Alternatively, cliniciansmay treat presumptive PAH with expensive and potentially harmfulmedications based on clinical and echocardiographic findings. Althoughcardiopulmonary exercise testing reveals differences in exhaled CO2 andventilatory efficiency between patients with PAH and PVH [34, 38], thistest is not available at the bedside, the required expertise is notfound at some institutions, and has limitations in non-ambulatorypatients.

Distinguishing pulmonary arterial hypertension (PAH) from other forms ofpulmonary hypertension (PH) such as pulmonary venous hypertension (PVH)can be difficult at the bedside, even with use of echocardiography orother non-invasive techniques. While recent reports have suggested apotential role for analysis of “notch” pattern in right ventricularoutflow tract Doppler flow velocity, right heart catheterization (RHC)with provocative procedures is usually required for accurate distinctionof PAH from PVH associated with non-systolic heart failure [28-31]. Thisdistinction is crucial as therapies for these two conditions andprognoses are different. Moreover, determining response to therapy inPAH is challenging with many well-described limitations of standardnon-invasive six minute walk test (6MWT) [30, 32], and logisticchallenges and expense with frequent RHC. Thus, there is a need forefficient, non-invasive testing of PE and distinguishing PAH from PVHand determining response to therapy in PAH is needed. A non-invasive,bedside test with good negative predictive value for PAH is a muchneeded diagnostic tool.

SUMMARY

The D-dimer test has been studied extensively in the exclusion of PE andits value in exclusion of low risk patients for further diagnosticevaluation is well established [1]. Despite a high negative predictivevalue in low risk patients [19], the D-dimer test has a highly variablesensitivity [20] and its interpretation can be confusing with multiplecommercially available tests and cut-off values [19]. Most importantly,D-dimer testing requires venipuncture and time for transport,measurement and reporting which may increase total healthcareexpenditure. A more rapidly available test would enhance speed ofdecision-making

End tidal carbon dioxide (EtCO₂) level measurement is a physiologicalsurrogate for diagnosing vascular obstruction resulting from PE.Pulmonary thromboembolism results in dead space ventilation andtherefore prevents meaningful gas exchange in the subtended lung unit,yielding an alveolar CO₂ content as low as zero mmHg. As a result,carbon dioxide content measured at end expiration, which representsadmixture of all alveolar gas, drops in proportion to dead spaceventilation. While there are many potential etiologies of increased deadspace ventilation including advanced chronic obstructive pulmonarydisease, these diseases are usually easily identified. Increased deadspace ventilation is not associated with common clinical conditions thatcan present similarly to pulmonary embolism e.g. unstable angina,gastroesophageal reflux. Dead space measurement and arterial-alveolarcarbon dioxide tension gradient have been studied in the evaluation ofPE [11-14], but the utility of end tidal CO₂ measurement alone indiagnosis of pulmonary embolism is not known. EtCO₂ is safe,non-invasive, inexpensive, and rapidly done at the bedside, whereas deadspace measurement requires collection of exhaled gas andalveolar-arterial gradient requires arterial blood gas sampling.

In an aspect of the invention, a system and method of evaluatingpulmonary embolism in a subject may include measuring carbon dioxidecontent at end expiration to obtain the end tidal partial pressure ofexhaled carbon dioxide in the subject, wherein the measurement is madeorally, obtaining a clinical approximation of dead space ventilationbased on the measurement, and excluding pulmonary embolism when the endtidal partial pressure of exhaled carbon dioxide reaches a threshold. Inthe method and system, the threshold is at least 36 mm Hg. The methodand system may further include applying a clinical prediction rule. Therule may include calculating a Wells score, and pulmonary embolism maybe excluded when the Wells score is at least four. In the method andsystem, the subject may be a pediatric subject. In the method andsystem, the subject may be sedated. In the method and system, thesubject may be intubated.

In an aspect of the invention, an oral capnometer may include an oralgas capture member, for collecting expired gases from the mouth, and acarbon dioxide measuring device attached to the oral gas capture memberfor determining levels of expired carbon dioxide from the mouth of asubject. In the method and system, the subject may be a pediatricsubject. In the method and system, the subject may be sedated. In themethod and system, the subject may be intubated. In the method andsystem, carbon dioxide levels may be measured continuously. In themethod and system, the expired carbon dioxide may be end tidal carbondioxide. In the method and system, the oral capnometer may be a portablecapnometer. Further, the capnometer may include an indicator that may beable to indicate the presence of diseases. Such an indicator may be avisual indicator, audio indicator, audio-visual indicator, a binaryindicator, and the like. In embodiments, the indicator may be indicativeof a particular diagnosis, such as PAH or PE.

In an aspect of the invention, a method of measuring end tidal carbondioxide in a subject may include collecting expired gases from the mouththrough an oral gas capture member adapted to be disposed on thesampling input of a carbon dioxide measuring device and a carbon dioxidemeasuring device attached to the oral gas capture member for determininglevels of expired carbon dioxide from the mouth of the subject. Inanother aspect of the invention, a method of measuring end tidal carbondioxide in a subject may include a carbon dioxide measuring device thatdirectly collects expired gases from the mouth of the subject by meansof an integral gas capture chamber. In the method and system, thesubject may be a pediatric subject. In the method and system, thesubject may be sedated. In the method and system, the subject may beintubated. In the method and system, the subject may be awake. In themethod and system, the subject may be spontaneously breathing. In themethod and system, carbon dioxide levels may be measured continuously.In the method and system, the expired carbon dioxide may be end tidalcarbon dioxide.

In an aspect of the invention, a system and method may comprise an oralgas capture member, for collecting expired gases from the mouth of asubject; a gas sensor for identifying and measuring at least one exhaledgas; and a housing for housing the gas sensor, wherein the housing isintegral with the oral gas capture member. In the system and method, theexhaled gas may be at least one of carbon dioxide, carbon monoxide,nitrogen, oxygen, and ketone. In the system and method, the subject maybe at least one of awake, spontaneously breathing, pediatric, sedated,intubated, sleeping, and the like. In the system and method, gas levelsmay be measured continuously. In the system and method, the expiredcarbon dioxide may be end tidal carbon dioxide. In the system andmethod, the gas sensor may also the measure pH of an exhaled gas.

In an aspect of the invention, an oral capnometer for measuringend-tidal carbon dioxide is provided. The capnometer may include anairway adapter, a filter, a sensor, and a display unit. The airwayadapter may be configured to allow passage of respiratory gases. In anaspect, the airway adapter may include a first port and a second port.The first port of the airway adapter may be dedicated for carbon dioxideintake. The second port of the airway adapter may be dedicated forpressure and temperature measurements. Further, the filter provided inthe capnometer may be connected to the airway adapter and may be able toseparate water from carbon dioxide. In addition, the sensor may enabledetection of respiratory parameters of the respiratory gases. In anaspect, the sensor may be a galvanic fuel cell. In another aspect, thesensor may be integrated in a mechanical pod. Further, the display unitmay be configured to the sensor for displaying waveforms thereon. In anaspect, the display unit may be able to display the waveforms through aninterface. In another aspect, the display unit may be an LCD display, anLED display, and the like.

In the method and the system, the oral capnometer may include an opticalbench to enhance stable, accurate measurements from a small sample. Theoral capnometer may also include a pulse oximeter that may be able tomonitor oxygen saturation of a patient's blood. In the method and thesystem, the oral capnometer may include a printer that may be able toprint measurement data. Further, the oral capnometer may also include aninterface option that may enable direct printing with an externalprinter. In the method and the system, the oral capnometer may furtherinclude an interface option that may function as a computer connectionport. In embodiments, the oral capnometer may include an interfaceoption for connection with a pulse oximeter. In the method and thesystem, the oral capnometer may be used with an R-series defibrillator.In the method and the system, the oral capnometer may also include analarm. The alarm may be preset for certain levels of end-tidal carbondioxide. In the method and the system, the oral capnometer may alsoinclude a turbine flow meter. The turbine flow meter may be a digitalturbine flow meter. Further, the turbine flow meter may bebidirectional. In an aspect, the turbine flow meter may require anantibacterial filter. In the method and the system, the oral capnometermay include a differential pressure transducer. The differentialpressure transducer may not require an antibacterial filter. In themethod and the system, the oral capnometer may further includesoftwarefor data management and reporting.

In embodiments, the oral capnometer may be a portable capnometer. In themethod and the system, the oral capnometer may be a handheld capnometer.In the method and the system, the oral capnometer may be light inweight. Further, the oral capnometer may be operated by means of one ofa battery and AC means.

In an aspect of the invention, an oral capnometer for measuring endtidal carbon dioxide is provided. The oral capnometer may also includean oral gas capture member, an end tidal carbon dioxide detectiondevice, and an indicator 1008. The oral gas capture member may collectexpired gases from the mouth. The end tidal carbon dioxide detectiondevice may be attached to the oral gas capture member and may determinelevels of the end tidal carbon dioxide at end expiration from the mouthof a subject. The end tidal carbon dioxide detection device may includea pressure sensor to determine pressure of the end tidal carbon dioxide.The indicator 1008 may be activated when the level of the end tidalcarbon dioxide falls below a pre-determined threshold value.

In an aspect of the invention, the oral gas capture member may collectexpired gases from the mouth at pre-determined regular intervals. In anaspect of the invention, the pressure sensor of the end tidal carbondioxide detection device is a differential pressure sensor. In an aspectof the invention, the end tidal carbon dioxide detection device may beconfigured to detect pulmonary arterial hypertension.

In an aspect of the invention, the end tidal carbon dioxide detectiondevice may be configured to detect a level of pulmonary arterialhypertension such that the level of pulmonary arterial hypertension maybe monitored over a time interval.

These and other systems, methods, objects, features, and advantages ofthe present invention will be apparent to those skilled in the art fromthe following detailed description of the preferred embodiment and thedrawings. All documents mentioned herein are hereby incorporated intheir entirety by reference.

All documents mentioned herein are hereby incorporated in their entiretyby reference. References to items in the singular should be understoodto include items in the plural, and vice versa, unless explicitly statedotherwise or clear from the text. Grammatical conjunctions are intendedto express any and all disjunctive and conjunctive combinations ofconjoined clauses, sentences, words, and the like, unless otherwisestated or clear from the context.

BRIEF DESCRIPTION OF THE FIGURES

The invention and the following detailed description of certainembodiments thereof may be understood by reference to the followingfigures:

FIG. 1 depicts an image of the modified capnometer of the invention.

FIG. 2 depicts a study flow diagram.

FIG. 3 depicts end tidal carbon dioxide in normal volunteers, patientswithout pulmonary embolism, and patients with pulmonary embolism.

FIG. 4 depicts end tidal carbon dioxide performance characteristics andpulmonary embolism diagnosis.

FIG. 5 depicts the oral gas capture member of the invention.

FIG. 6 depicts the invention in which the gas capture chamber forms anintegral part of the capnometer.

FIG. 7 depicts the invention in which the gas capture chamber isdetachably attached to the capnometer, such that other measuring devicesmay be attached to the gas capture chamber.

FIG. 8 depicts a flow chart of a method for excluding pulmonaryembolism.

FIG. 9 depicts a flow chart of a method of measuring end tidal carbondioxide in a subject.

FIG. 10 depicts an image of a modified capnometer of the invention.

FIG. 11A depicts end tidal carbon dioxide performance characteristicsand pulmonary arterial hypertension diagnosis.

FIG. 11B depicts a study flow diagram.

FIG. 12 depicts end tidal carbon dioxide characteristics and specificityof pulmonary arterial hypertension diagnosis.

FIGS. 13A-13F depict correlation of end tidal carbon dioxide with otherinvasive hemodynamic procedures.

FIG. 14 depicts effects of testing parameters on measurement of endtidal carbon dioxide.

FIGS. 15A-15C depict effect of exercise on the ETCO2 in PAH, PVH, andnon PH patients.

FIG. 16 depicts that PAH patients, who had functional class III, haddecreased EtCO2 after 6MWT as compared to patients with functional classII.

FIG. 17 depicts that in PAH patients, resting EtCO2 did not correlatewith 6MWT distance.

FIG. 18 depicts effects of therapy on pulmonary arterial hypertension.

FIG. 19 depicts a flow chart of a method for diagnosing pulmonaryarterial hypertension.

FIG. 20 depicts a system for measuring end tidal carbon dioxide.

FIG. 21 depicts a device for measuring end tidal carbon dioxide.

FIG. 22 depicts a system for measuring end tidal carbon dioxide.

FIG. 23 depicts a flow chart of a method related to diagnosing pulmonaryarterial hypertension.

FIG. 24 depicts a flow chart of a method related to diagnosing pulmonaryarterial hypertension.

FIG. 25 depicts a flow chart of a method related to diagnosing pulmonaryarterial hypertension.

DETAILED DESCRIPTION

End tidal CO2 detection may be used to differentiate pulmonary arterialhypertension (PAH) patients from those with normal pulmonary bloodvessels or pulmonary venous hypertension patients as well as to diagnosepulmonary embolism (PE) in patients. A carbon dioxide measurement andanalysis device enables emergent evaluation of PE patients andoutpatient management of PAH patients. For example, the rise in endtidal carbon dioxide can be used to detect successful therapy inpatients with established PAH, which has not been demonstratedpreviously.

The present disclosure also concerns an oral capnometer 102 formeasuring end tidal carbon dioxide content as it is exhaled from themouth. Sampling orally exhaled gases may comprise using a capnometer orcapnograph with an adaptor on the sampling input to enable oralsampling, as in FIG. 1, an integral oral gas capture member as in FIG.6, or a detachably engaged oral gas capture member as in FIG. 7. Forexample, the oral capnometer 102 may be attached to plastic tubing withan adapter that is placed in the mouth. The adapter may be sized tosample gases exhaled from the oral cavity. In other embodiments, thepresent invention may be an integral oral gas capture member 602 inwhich the capturing space is connected integrally to the capnometer. Instill other embodiments, the oral sampling space may be interchangeablyattached to the capnometer to facilitate measurements of exhaled gassesfrom subjects of various sizes or states of health. Sampling gases fromthe mouth instead of the nose enables more accurate measurement ofexhaled gases as nasal sampling may cause hyperventilation. For exampleand without limitation, oral sampling of exhaled gases may enable moreaccurate measurements of end tidal carbon dioxide (EtCO₂), andtherefore, more accurate estimation of dead space ventilation.

By measuring EtCO₂2 in patients undergoing evaluation for PE withoutcontrolling clinical care or management, predictions may be maderegarding PE status. For example, EtCO₂ may be reduced in patients withPE and a normal EtCO₂ measurement may have a high negative predictivevalue to exclude PE.

The oral capnometer 102 may also be useful for measuring exhaled oxygenlevels, such as for estimating cardiac output or other metabolicequivalents. The oral capnometer 102 may also be useful for measuringexhaled carbon monoxide levels, such as in the detection of ongoingcigarette smoking, carbon monoxide poisoning, and the like. The oralcapnometer 102 may also be useful for measuring exhaled residualcompounds left in the lungs to aid in the diagnosis of some cancers. Theoral capnometer 102 may also be useful for measuring exhaled ketones,such as in the diagnosis of ketoacidosis. The oral capnometer 102 mayalso be useful for measuring the pH of exhaled gas for diagnosis ofmetabolic acidosis in lactic acidosis or diabetic ketoacidosis. The oralcapnometer 102 may also be useful for measuring exhaled nitrogen. Theoral capnometer 102 may comprise a gas sensor that is capable ofmeasuring many different gases and pH levels. Alternatively, each gasmay be sensed by an individual gas sensor housed separately. Thus, theoral gas capture member 702 may be detachably associated, as shown inFIG. 7 for two devices measuring “Gas A” and “Gas B”, with the oralcapnometer 102 such that if measurement of a gas with another gassensing device is required, the oral gas capture member may be attachedto and used with the device. In an embodiment, multiple sizes and shapesof oral gas capture members, suitable for subjects of different ages,sizes and physical conditions, may be detachably attached to the oralcapnometer 102.

In order to demonstrate the usefulness of accurate end tidal carbondioxide sampling, the oral capnometer 102 of the invention was used indefining the optimal end tidal carbon dioxide (EtCO₂) level in theexclusion of pulmonary embolism (PE) in patients undergoing evaluationof possible thromboembolism. The oral capnometer 102 of the inventionwas used in a study involving 298 patients conducted over 6 months at asingle academic center. EtCO₂ was measured within 24 hours of contrastenhanced helical CT, lower extremity duplex or ventilation/perfusionscan. Performance characteristics were measured by comparing testresults with clinical diagnosis of PE. The results of the study usingthe oral capnometer 102 were that PE was diagnosed in 39 patients (13%).FIG. 3 depicts mean end tidal carbon dioxide±SD in healthy volunteers,patients without pulmonary embolism (no pulmonary embolism) and patientswith pulmonary embolism (pulmonary embolism). The data had a p<0.05 vs.healthy volunteers and no pulmonary embolism group. The mean EtCO₂ inthe healthy volunteers was not different from EtCO₂ in the enrolledpatients without PE (36.3±2.8, SD mmHg vs. 35.5±6.8 mmHg), as shown inFIG. 3. EtCO₂ in the patients with PE was 30.5±5.5 mmHg (p<0.001 versusno PE group). EtCO₂ of ≧36 mmHg had optimal sensitivity and specificity(87.2 and 53.0% respectively) with a negative predictive value of 96.6%(92.3-98.5 95% CI). This increased to 97.6% (93.2-99.2 95% CI) whencombined with a Wells score <4. EtCO₂ of ≧36 mmHg may reliably excludePE. Accuracy is augmented by combination with a Wells score. EtCO₂ maybe prospectively compared to D-dimer in accuracy and simplicity toexclude PE.

All patients ≧18 years of age who were seen in the Emergency Departmentor inpatient wards at an academic university hospital over the six monthperiod were screened electronically for a computer order for contrastedchest helical CT, ventilation-perfusion lung scan, pulmonary angiogramor lower extremity Duplex evaluation. Patients meeting screeningcriteria were approached for consent to undergo EtCO₂ within 24 hours ofstudy order placement. Exclusion criteria were inability to consent,pregnancy, known hypercarbic respiratory failure, mechanicalventilation, face mask oxygen or more than 5 L/minute nasal cannulaoxygen or known neuromuscular disease. Patients who presented forevaluation more than once could be enrolled multiple times (n=5, twostudies each).

EtCO₂ was measured by a trained single tester blinded to diagnosis usingthe oral capnometer 102 of the invention [15]. The device may becalibrated to ±2 mmHg up to 38 mmHg and ±0.08% for every 1 mmHg over 40mmHg. The oral capnometer 102 is different from capnometers used tomeasure exhalation from the nostrils in that the uptake cannula isinserted into a plastic tube that, when placed in the mouth, may enablepatients to tidally breathe while CO₂ is measured, as shown in FIG. 1.CO₂Patients were instructed to breathe normally and were tested for fivebreaths in either a supine or seated position. Nostrils were not clippedshut. EtCO₂ for each breath and respiratory rate were measured. The oralcapnometer 102 of the invention was validated every two weeks at twolevels of CO₂ using an exercise machine calibrated to zero and 5.6% CO₂.Patient charts were analyzed for demographic data including comorbidconditions and thromboembolic risks, self-reported race/ethnicity(categorized into Hispanic, African-American, Caucasian, or other)results of serum chemistries, blood counts, ventilation/perfusion lungscan, CT (such as Brilliance CT 64 Channel, Phillips, Amsterdam, TheNetherlands), pulmonary angiography, and venous duplex exams. Wellsscore [6] was assigned by a single physician, blinded from finaldiagnosis, from data obtained at the time that diagnostic tests wereordered. Plasma D-dimer testing (STA LIATEST, Diagnostica Stago,Parsippany, N.J.[16]) was performed at the discretion of the treatingphysician. Patients with D-dimer testing alone for PE were not includedin this study because of the risk of false positive D-dimer tests.

Pulmonary embolism was defined by a published consensus criteria [1]including positive contrast-enhanced CT, intermediate or highprobability ventilation perfusion lung scan (as described in PIOPED I[17]) combined with high pretest probability, or positive lowerextremity duplex examination with a high clinical suspicion for PE.

To ensure accuracy and reproducibility, and to standardize the modifiedsensing device, and discover stability of EtCO₂ measurements over timein healthy individuals, EtCO₂ was measured for five breaths in 24healthy volunteers (mean age 40.0 (12.0), 10/24 male) on three differentdays. Additionally, EtCO₂ was measured with different FiO₂ delivered bynasal cannula up to 51 pm and found no difference (data not shown).

Based on the study center's experience and previous work [8, 18], a 15%positive rate of diagnostic tests for patients undergoing PE evaluationwas assumed. Given this diagnostic rate and a standard deviation of 2.8mmHg in EtCO₂ measurements in normal volunteers, a sample sizecalculation determined that 300 patients would be required to detect adifference in EtCO₂ of 1.3 mmHg between groups with 80% power at analpha level of 0.05. This sample size would allow detection of adifference of 9% in sensitivity compared to the Wells score <4[6].Continuous variables are reported as mean (standard deviation) andanalyzed using Student's t-test or Wilcoxon Rank Sum testing.Categorical variables are reported as percentages and were analyzedusing Fisher's Exact test. Receiver Operating Characteristic (ROC)curves with area under the curve (AUC) were used for determining theoptimal EtCO₂ to discriminate between patients with and without PE. Allp-values are two-tailed and values ≦0.05 were considered significant.Data analyses were done using both R version 2.7.1 and SPSS (Version15.0; Chicago, Ill., USA).

Referring to FIG. 2, a study flow diagram is shown. The study flowdiagram shows that, at step 201, a total of 335 patients were screenedand approached for entry into the trial. At step 203, twenty patientsdid not consent. At step 205, of the 315 patients in whom EtCO₂ wasmeasured, 17 patients were excluded at step 207 after enrollment (twowere found to be pregnant and 15 did not have any imaging studies, as inFIG. 2. At step 209, of the remaining 298 patients included in the finalanalysis, 269 patients had CT angiograms at step 211, 17 patients hadV/Q scans at step 213, and 92 had lower extremity (LE) dopplerexamination at step 215. 39 patients were diagnosed with pulmonaryembolism (34 positive helical CT, three intermediate or high probabilityventilation perfusion scans with high clinical suspicion, two positivelower extremity duplex examinations with high clinical suspicion). Fivepatients were enrolled twice. One hundred eighty patients were enrolledfrom the Emergency Department with 21 PEs and 118 were inpatients with18 PEs.

Demographic characteristics of the group as a whole and thesub-categories of those with and without PE are shown in Table 1 (Dataare presented as mean±SD unless otherwise stated, n=298 unless otherwisestated, p values are for No PE vs. PE groups.)

TABLE 1 Demographics All No PE (n = 298) (n = 259) PE (n = 39) p ValueAge (yrs) 52.1 ± 51.0 ± 59.5 ± 0.004 17.2 17.1 16.05 Gender (% female)53 54 46 0.36 Race (%, n = 294) White 72 72 77 African-American 25 25 23Other 3 3 0 Smoking (%, n = 290) Never 53 53 54 0.39 Current 32 33 24Past 15 14 22 Comorbidities (%) None 33 33 31 0.17 Diabetes 3 2 10Hypertension 25 25 23 Diabetes + hypertension 13 14 8 Cancer 13 12 15Chronic lung disease 6 7 3 Other 7 7 10 PE Risk Factors (%) None 62 6818 <0.001 Post-operative 4 4 5 Cancer 13 12 18 Post-partum 1 1 0Immobilized 3 2 8 Previous DVT/PE 8 7 13 Multiple 8 4 33 Other 1 0 5

There was no difference in age, gender, ethnicity, smoking status orpresence or absence of medical comorbidities in the two groups. Thegroup with PE was significantly enriched for the presence of one or morerisk factors for venous thromboembolic disease than the no PE group(p<0.001). The group without PE had a range of diagnoses from no causeidentified (n=44, 17%), pulmonary disease such as COPD, asthma or lungcancer (n=84, 32%), and cardiac disease (n=48, 19%) to musculoskeletaldisease, neuromuscular disease, and deep venous thrombosis without PEwhich made up the remainder.

Patients with PE were less likely than those without PE to undergo chestCT imaging for chest pain alone (p=0.01 PE vs. No PE groups, Table 2),however there were no significant differences in the other indicationsfor chest imaging between the two groups. (Data are presented as mean±SDunless otherwise stated, n=298 unless otherwise stated, p values are forNo PE vs. PE groups.) The mean Wells score was 4.3±2.5 in the group withPE and 1.7±1.9 (p<0.001) in the no PE group. Five of 39 patients with PEhad a Wells score ≦2.0. Fourteen percent of CTs in the emergencydepartment were positive for PE and 17% of CTs ordered as an inpatientwere positive for PE. 97/298 patients had serum D-dimer measured, ofthese 47 were negative (0 PEs) and 48 positive (4 PEs).

TABLE 2 Presenting Features of Study Enrollees No PE All (n = 298) (n =259) PE (n = 39) p Value Indication for PE evaluation (%) Chest pain 3537 23 0.006 Hypoxemia 1 0 5 Dyspnea 25 24 31 Hemoptysis 0 0 3 Fever 6 65 Chest pain and 9 8 15 dyspnea Limb swelling/pain 4 4 3 Miscellaneous20 21 15 Wells score  2.0 ± 2.1  1.7 ± 1.9  4.3 ± 2.5 <0.001 Heart rate(bpm)  86.2 ± 17.1  86.0 ± 17.1  87.8 ± 15.0 0.42 Systolic blood 125.3 ±20.7 126.3 ± 21.0 118.7 ± 17.0 0.02 pressure (mmHg) Diastolic blood 72.2 ± 14.5  72.5 ± 15.0  70.4 ± 10.5 0.37 pressure (mmHg) Respiratoryrate 17.2 ± 6.2 17.0 ± 6.3 18.6 ± 5.6 0.09 (bpm) Oxygen 96.6 ± 2.6 96.6± 2.6 96.4 ± 2.3 0.39 saturation (%) Supplemental 26 24 44 0.01 oxygen(%)

In normal volunteers, mean EtCO₂ was 36.3±2.8 mmHg (95% CI 35.1-37.4,Table 3). Data are presented as mean±SD, n=24. There were no significantdifferences among the five measured breaths each day or among the meanEtCO₂s in an individual over the three separate days. Age and gender didnot affect EtCO₂.

TABLE 3 EtCO₂ in normal individuals over 5 separate days Age (yrs)  40.0± 12.0 Female no. 14 Smoking no. Never 20 Past 4 Current 0 EtCO₂ bybreath (Day 1) (mmHg) p = 0.21 Breath 1 36.7 ± 3.0 Breath 2 36.3 ± 2.9Breath 3 36.7 ± 3.0 Breath 4 37.1 ± 3.5 Breath 5 37.3 ± 3.6 EtCO₂ by day(mmHg) p = 0.25 Day 1 36.6 ± 3.0 Day 2 36.6 ± 3.8 Day 3 35.6 ± 3.6Overall mean EtCO₂ (mmHg) 36.4 ± 2.8

There was no significant difference in EtCO₂ between normal controls andthe no PE group (36.3±2.8 mmHg vs. 35.5±6.8 mmHg respectively, p=0.56,FIG. 3). The group with PE had a significantly lower EtCO₂ (30.5±5.5mmHg, vs. healthy volunteers p<0.001), which was also significantcompared with the no PE group (P<0.001). Mean EtCO₂ was not different inthe two D-dimer groups (35.3±5.9 mmHg D-dimer positive vs. 36.1±5.2 inD-dimer negative groups, p=0.35). There were no adverse events relatedto EtCO₂ measurement.

A receiver operator characteristics (ROC) curve demonstrating theability of EtCO₂ to discriminate between patients with and without PEand the corresponding sensitivities and specificities to a given EtCo₂measurement are shown in FIG. 4 (AUC=0.739). In order to avoid the mostunnecessary procedures in the diagnosis of PE while maintaining optimalsensitivity for diagnosis, a cut off of 36 mmHg was chosen for furtheranalysis of the characteristics of this test. At this cut off, thenegative predictive value was 96.6% (95% CI 92.3-98.5, Table 4).

TABLE 4 Test performance characteristics Positive Negative PredictivePredictive Sensitivity Specificity Value Value (%, 95% CI) (%, 95% CI)(%, 95% CI) (%, 95% CI) EtCO₂ <36 All 87.2 53.0 21.1 96.6 Comers(73.3-94.4) (47.0-58.8) (15.5-28.1) (92.3-98.5) EtCO₂ <36, 91.9 49.021.1 97.6 excluding >44 (78.7-97.2) (42.8-55.2) (15.5-28.1) (93.2-99.2)Wells 61.5 83.3 34.8 93.8 Score ≧4 (45.9-75.1) (78.4-87.3) (24.6-46.6)(89.9-96.2) EtCO₂ <36 All 92.3 45.2 19.6 97.6 Comers + (79.7-97.3)(39.4-51.1) (14.5-25.9) (93.2-99.2) Wells Score ≧4

When patients with EtCO₂≧36 mmHg but <44 mmHg (2.78 SD above normal)were analyzed, there was an increase in negative predictive value to97.6% (95% CI 93.2-99.2). A negative predictive value for Wells score<4of 93.8% (95% CI 89.9-96.2) was found in this population. In combiningthe Wells score<4 with the EtCO₂>36 mmHg without restriction on maximumEtCO₂, the negative predictive value again rose to 97.6% (95% CI93.2-99.2).

In this study, it was shown that a safe, simple, inexpensive, bedsidetest for EtCO₂ has a high negative predictive value in excluding PE andthat the EtCO₂ measured with the oral capnometer 102 of the invention incombination with the Wells Score improves negative predictive value to avery high level of accuracy.

Dead space fraction (Vd/Vt), measured by comparing total exhaled partialpressure CO₂ (pCO₂) with arterial partial pressure CO₂ (paCO₂), haspreviously been shown to be abnormal in pulmonary embolism and Vd/Vt incombination with D-dimer testing is effective at ruling out PE [11-13,21]. However, the requirement of specialized equipment and an arterialpuncture limit its widespread adaptation. EtCO₂ measured only with theoral capnometer 102 is a surrogate for dead space measurement.

Various cut off levels of EtCO₂ were examined to determine optimalsensitivity and specificity of this test. Using a cut off of ≧36 mmHg, anegative predictive value of 96.6% was achieved, which is similar tothat reported with d-dimer testing [19]. There was a small improvementafter excluding patients with an EtCO₂ significantly outside of therange of normal, but might confuse clinical decision-making without aconcomitantly large improvement in test characteristics. The addition ofthe Wells score<4 to the EtCO₂ measurement similarly numericallyimproved the testing characteristics without adding further confusionabout patient exclusions. It was found that at the lower levels ofEtCO₂, there was a substantial increase in specificity for PE. Thisimproved specificity at lower EtCO₂ levels is in marked contrast withD-dimer, with results that are either positive or negative.

In the study group, 166 subjects had an EtCO₂>36 mmHg and would not haveundergone further testing if that were used as the sole criterion forruling out PE. Of these 166 subjects, 20 had a Wells score of 4.0 orhigher. Thus, in the study, 146/298 (49%) of subjects would have beenspared further evaluation for PE using these criteria. Three of 39 PEswould be missed in the study using these criteria. All three of thesepatients were discovered to have hypoventilation after furtherevaluation during the hospitalization (morbid obesity, chronic narcoticuse and interstitial lung disease).

The importance of sparing these diagnostic procedures is not trivial. Inthe cohort, 226 patients (76%) underwent diagnostic CT scanning Thelong-term risks of exposure to radiation from chest CT scanning are aconcern [4, 9, 22, 23]. The typical contrast-enhanced chest CT forpulmonary embolism evaluation delivers approximately 20 mSv of radiation[4, 24]. This dose from a single CT approaches the 40 mSv widely thoughtof as a dangerous limit from historical data [4, 22, 24]. In this studyalone, five people were enrolled twice in the six-month study. Whilethere is debate about the “safe limit” of radiation exposure, theAmerican College of Radiology has called for controlling unnecessaryradiation exposure [23]. The monetary savings from preventingunnecessary CT studies is also potentially substantial. For example, ata cost per study of $1739 [25], patients in the study underwent a totalof 226 contrast enhanced helical CTs, 120 of which could potentially bespared saving $208,680. The study included both inpatients and patientsin the Emergency Department to capture the complete population perceivedto be at risk for PE. Because patients who underwent only D-dimertesting were not included, the pre-test probability for PE in the cohortmay have been increased. Despite this potential bias, EtCO₂ was similarin the normal controls and the group without PE, suggesting thatphysiologically the group without PE was similar to normals. Too fewpatients had PEs in the group with D-dimer data to allow a meaningfuldirect comparison with EtCO₂. While the CT positivity rate for PE waslower than some prior published reports [7, 8, 26], it is similar toother publications in the literature and may represent local practicepatterns [21, 27]. The EtCO₂ would likely be abnormal in conditionsaffecting metabolic activity or carbon dioxide excretion such aspregnancy, end-stage chronic obstructive lung disease or advancedneuromuscular disease; therefore patients known to have these conditionsfrom participation were excluded, totaling fewer than 10 patients.Thyroid disease at its extremes may affect EtCO₂ results, but this isoften not known at initial evaluation, thus these patients were notexcluded. EtCO₂ cannot distinguish between type of pulmonary arterialobstruction such as acute PE, chronic thromboembolic disease or tumoremboli. No CT angiograms showed changes typical for chronicthromboembolic pulmonary hypertension.

Thus, a cheap, simple, readily available, non-invasive test of EtCO₂combined with a bedside prediction tool may be useful to excludepulmonary embolism in patients without pregnancy or advanced lung orneuromuscular disease.

Accurate measurement of orally exhaled gases may be useful additionallyin a pediatric population, with patients under sedation, with patientswho have been intubated, to measure expired gases continuously, and thelike.

The oral capnometer 102 of the invention may be constructed by adaptingthe sampling input of a capnometer, as shown in FIG. 1, with an oraladaptor. For example, the oral adaptor may be a hollow-bodied oral gascapture member that sits in a subject's mouth, having formed in themember an aperture through which a subject may exhale gases and anaperture for placement of a sampling tube of the capnometer thatpositions the sampling tube within the capture member and allows exhaledgases to enter the sampling tube. In embodiments, the adaptor may be ofany shape and may bear any markings For example, as in FIG. 5, thesampling tube may be placed through a hole in the sidewall of a hollowtube. In an embodiment, the tube may have dimensions of 1.5 cmdiameter×5 cm length. The sampling tube may be formed from flexible,plastic tubing. The oral gas capture member may be formed from anysuitable material, such as plastic, metal, glass, or the like. In anembodiment, the oral gas capture member may be disposable.

The oral capnometer 102 may be used to construct a capnograph bymeasuring carbon dioxide levels over time.

The oral capnometer 102 may be useful in measuring carbon dioxide levelsin order to estimate cardiac output and metabolism; diagnosehypoventilation, bronchitis, emphysema, asthma, congenital heartdisease, hypothermia, diabetes, circulatory shock; and obtaininformation about the effectiveness of CPR and the return of spontaneouscirculation (ROSC), CO₂ production, pulmonary (lung) perfusion, alveolarventilation, respiratory patterns, and elimination of CO₂ from theanesthesia breathing circuit and ventilator.

In an embodiment, evaluating pulmonary embolism in a subject may includemeasuring end tidal partial pressure of exhaled carbon dioxide in thesubject, wherein the measurement is made orally, obtaining a clinicalapproximation of dead space ventilation based on the measurement, andexcluding pulmonary embolism when the end tidal partial pressure ofexhaled carbon dioxide reaches a threshold. The threshold may be atleast 36 mm Hg. The evaluation may further include applying a clinicalprediction rule. The rule may include calculating a Wells score, andpulmonary embolism may be excluded when the Wells score is at leastfour. The subject may be a pediatric subject, sedated, intubated, andthe like.

In an embodiment, an oral capnometer 102 may include an oral gas capturemember 104, 602, 702, for collecting expired gases from the mouth, and acarbon dioxide measuring device attached to the oral gas capture member104, 602, 702 for determining levels of expired carbon dioxide from themouth of a subject. The subject may be a pediatric subject, sedated,intubated, and the like. Carbon dioxide levels may be measuredcontinuously. The expired carbon dioxide may be end tidal carbondioxide.

In an embodiment, a method of measuring end tidal carbon dioxide in asubject may include collecting expired gases from the mouth through anoral gas capture member 104, 702 adapted to be disposed on the samplinginput of a carbon dioxide measuring device and determining levels ofexpired carbon dioxide in the expired gas. In another embodiment, amethod of measuring end tidal carbon dioxide in a subject may include acarbon dioxide measuring device that directly collects expired gasesfrom the mouth of the subject by means of an integral gas capturechamber 602. The subject may be a pediatric subject, sedated, intubated,awake, spontaneously breathing, and the like. Carbon dioxide levels maybe measured continuously. The expired carbon dioxide may be end tidalcarbon dioxide.

In an embodiment, an oral capnometer 102 may include an oral gas capturemember 602 for collecting expired gases from the mouth of a subject; agas sensor for identifying and measuring at least one exhaled gas; and ahousing for housing the gas sensor, wherein the housing is integral withthe oral gas capture member 602. The exhaled gas may be at least one ofcarbon dioxide, carbon monoxide, nitrogen, oxygen, and ketone. Thesubject may be at least one of awake, spontaneously breathing,pediatric, sedated, intubated, sleeping, and the like. Gas levels may bemeasured continuously. The expired carbon dioxide may be end tidalcarbon dioxide. The gas sensor may also the measure pH of an exhaledgas.

Referring to FIG. 8, a method of evaluating pulmonary embolism in asubject may include measuring a carbon dioxide content at end expirationto obtain an end tidal partial pressure of carbon dioxide in the subject802 and excluding pulmonary embolism when the end tidal partial pressureof exhaled carbon dioxide reaches a threshold 804. The measurement maybe made orally. A clinical approximation of dead space ventilation isbased on the measurement. The threshold may be at least 36 mm Hg. Themethod of evaluating pulmonary embolism may further include applying aclinical prediction rule. The rule may include calculating a Wellsscore. Pulmonary embolism is excluded when the Wells score is at leastfour. The subject may be at least one of sedated, intubated, andpediatric.

Referring to FIG. 9, a method of measuring end tidal carbon dioxide in asubject may include collecting expired gases from the mouth through anoral gas capture member adapted to be disposed on the sampling input ofa carbon dioxide measuring device 902 and determining levels of expiredcarbon dioxide in the expired gas 904. The subject is at least one ofsedated, intubated, and pediatric. The carbon dioxide levels may bemeasured continuously. The expired carbon dioxide may be end tidalcarbon dioxide.

Further, the capnometer may include an integrated sensor or sensor arraythat may be able to detect the presence of a disease. Integrated sensorsenable the measurement and characterization of other respiratory gascomponents, some of which may be indicative of disease. For example, anintegrated sensor may be able to detect elevated levels of acetone inthe exhaled breath for a preliminary diagnosis of diabetes. In anotherexample, a sensor for detecting nitric oxide may be able to detect thepresence of asthma. In embodiments, the sensor may be a sensor operableto detect chemicals in exhaled breath, in the saliva, in the blood, onthe skin, in the urine, and the like. In embodiments where the sensor isnot for measuring exhaled breath components, the sensor may beintegrated in a part of the capnometer readily accessible by a user forcarrying out the measurement.

When the sensor detects a disease, an indicator 1008 may be activated.Such an indicator may be a visual indicator, audio indicator,audio-visual indicator, a binary indicator, and the like.

The capnometer may include an airway adapter, a filter, a sensor, and adisplay unit. The airway adapter may be configured to allow passage ofrespiratory gases. For example, a first port of the airway adapter maybe dedicated for carbon dioxide intake, while a second port of theairway adapter may be dedicated for pressure and temperaturemeasurements. Further, the filter provided in the capnometer may beconnected to the airway adapter and may be able to separate water fromcarbon dioxide. In addition, the sensor may enable detection ofrespiratory parameters of the respiratory gases. In an aspect, thesensor may be a galvanic fuel cell. In another aspect, the sensor may beintegrated in a mechanical pod.

The display unit may be configured to the sensor or sensor array fordisplaying waveforms thereon. In an aspect, the display unit may be ableto display the waveforms through an interface. In another aspect, thedisplay unit may be an LCD display, an LED display, and the like.

In an embodiment, the oral capnometer may include an optical bench toenhance stable, accurate measurements from a small sample. In anexample, a low sample flow rate of 50 ml/min may allow monitoring a widerange of patients with the oral capnometer without compromising on theresponse time. The oral capnometer may be adapted to monitor EtCO2 forintubated or non-intubated neonatal through adult patients. In anotherembodiment, the oral capnometer may include a user interface that may beuseful for displaying waveforms and trends. The waveforms and trends mayinclude but are not limited to capnographic waveforms and trends, SpO2graphical trends, and plethysmographic waveforms. Further, the userinterface may be used for setting user-adjustable alarms. In anembodiment, the user interface may have menus in multiple languages sothat the user may select a language of his/her choice. Further, the userinterface may enable data output and printing, and the like.

In embodiments, the oral capnometer may include pulse oximetrytechnology. The oral capnometer may handle moisture with the help of anintegrated water separation filter in each connector and a multi-portairway adapter design as well as no cross-sensitivity to other gases,such as anesthetic agents. The oral capnometer may warm-up quickly andrequire no routine calibration. The oral capnometer may further includea first port for CO₂ and a second port that may be used for invasivepressure or temperature. The oral capnometer may be embodied in aportable, handheld form factor that may weigh less than two pounds andmay be operated by AC, battery, and the like.

In embodiments, CO2 detectors may be used to detect approximate rangesof EtCO2 in adult and infant intubated patients to assist in theverification of tube placement during endotracheal or nasotrachealintubation. The detectors may be attached to the endotracheal tube toprovide breath by breath visual feedback on the levels of exhaled CO2.The visual feedback may include a color change method from purple toyellow. In an example, the purple color is indicative of 0.03% to 0.5%CO2 in the breath, the tan color is indicative of 0.5% to 2% CO2 in thebreath and the yellow color is indicative of 2% to 5% CO2 in the breath.

In an embodiment, if the endotracheal tube is placed correctly thevisual feedback may be alternate between purple and yellow colors. Inembodiments, an adult detector may be used for patients weighing morethan 15 kg. The adult detector may weigh less than 20 g, and may have aninternal volume of 25 cc. Further, a pediatric care detector may be usedfor patients weighing from 1 to 15 kg. Such a detector may weigh 5 gramsand may have an internal volume of 3 cc. The detectors (adult andpediatric) may have two connection ports. One connection port may beconnected to the endotracheal tube and the other end may be connected tothe resuscitation bag. Both the detectors are small and are meant forsingle usage and may be used for up to two hours.

In an embodiment, the oral capnometer may include an optical bench thatmay provide stability during cold temperatures making the oralcapnometer good for use during patient transport. The oral capnometermay also be used for clinical settings where fast and easy EtCO₂monitoring may be required. The oral capnometer may be equipped withfast, first breath EtCO₂ technology that may provide measurement datawith the first breath. Further, the oral capnometer may be used forendotracheal tube placement verifications, waveform trend monitoring,detecting breathing irregularities, gauging the efficacy of CPR andprocedural sedation monitoring. The oral capnometer's sidestream designmay allow it to be used with both intubated and non-intubated neonatalthrough adult patients. The oral capnometer may provide EtCO₂, FiCO₂,respiratory rate and CO₂ waveform data using a simple serial protocol.The oral capnometer may use advanced algorithms that may adjust for CO₂absorption, temperature, pressure, altitude, and respiration rate. Inaddition, the oral capnometer may require no interruption to compensatefor drift. The oral capnometer may function quietly and may havedimensions of 60×96×25 mm. The oral capnometer may weigh 32 g with a 21g pump plus tubing & water trap. Further, the oral capnometer may have aflow of 75 ml/min.

In embodiments, a cardiopulmonary testing system may be used in clinicalsettings for early detection of heart conditions and to manage heartfailure disease. The system may include a device that may include a dataanalyzer, a disposable patient interface or mask, a pulse oximeter, acomputer, and a printer. Further, the system may measure ventilatory gasparameters, VE/CO2 slope, and chronotropic indices while the patient mayexercise for a certain period of time. In a test, four to five therapysettings of a patient are tested. At the end of the test, thecardiopulmonary testing system may use a computer algorithm to rank thephysiological response to exercise at each setting. In an embodiment,the system may provide real time data interpretations. In an aspect ofthe present invention, the system may be used to quantify a patient'sfunctional capacity, assess patient risk, and obtain a trend of thepatient's response to therapy over time. The system may also be used toconduct different tests such as low-intensity graded protocol exercisetest, a standard incremental protocol exercise test, and a steady statetest. In addition, the cardiopulmonary testing system may measurecardiopulmonary gas exchange without any undue strain on the patient andmay be used in clinical settings by any trained clinical employee.

In an embodiment, the device may perform cardiopulmonary exercise testsand displays results on a color LCD user interface with the option ofprinting the results. The device may also measure forced vital capacity,maximum voluntary ventilation, pre & post bronchial dilator response,and slow vital capacity (inspiratory & expiratory). The device mayinclude a sensor that may be a galvanic fuel cell. Further, the devicemay use a dynamic mixing chamber. In an exemplary embodiment, the devicemay be used in clinical settings for all ages. Further, the device mayhave a flow range of 0.08-2.0 1/s. In an embodiment, the device mayweigh 1.5 kg and may have 24×20×8 cm dimensions.

In an aspect, the device may be a hand held device designed for flexiblespirometry screening for all age groups. The device may be used toperform tests easily and accurately wherever it is needed. The resultsof the tests conducted by the device may be viewed on a user interface.The user interface may be a black and white LCD display. In anembodiment, the results may also be printed by linking the devicedirectly to an external printer or to a PC through a USB port. Further,the device may be a portable spirometer designed to measure ventilatorySpO2 and HR parameters. The device may also measure forced vitalcapacity, maximum voluntary ventilation, bronchial dilator test, thebronchial challenge test, and the like. In an embodiment, the device maybe used in clinics by primary care practitioners, in mobile clinicalsettings, as a preventative measure, in sports medicine, and the like.The device may provide three USB interfacing options for direct printingwith an external inkjet or laser printer (PCL compatible). The USBinterfacing options may also be used as PC connection port, forconnection with pulse oximeter for SpO2 monitoring, and the like.

Further, the device may be available in three different configurations.A first configuration may be a basic model of the device that mayinclude a bidirectional digital turbine flow meter. The digital turbineflow meter may require use of antibacterial filters. In an embodiment,in a second configuration, the device may be available as a disposabledevice that may have a single use differential pressure transducer. Thedifferential pressure transducer may be designed to avoid risk of crosscontamination especially in hospital settings. Further, the differentialpressure transducer may not require antibacterial filter. A thirdconfiguration of the device may include a turbine flow meter and asilicone face mask with head cap and SpO2 monitor. The SpO2 monitor maymeasure ventilatory parameters and oxygen saturation during a “sixminute walking test”.

In embodiments, the device may come with PC software that may be usedfor data management and reporting. The device may include an internalmemory which may store up to 1000 tests/patients. In an exemplaryembodiment, the device may be a hand held device with a compact size of18×7.5×3 cms and may weigh less than 400 gram. The device may beembodied in a simple operating mode through a navigation tool similar tocellular phones. The device may also be equipped with a rechargeablebattery that may last up to 6 hours.

In embodiments, the device may be embodied in a mechanical pod and maybe used as a non-invasive device for intensive care monitoring ofendotracheal EtCO2. Further, the sensor and the mechanical pod mayintegrate respiratory parameters, waveforms and flow loops withhemodynamic data on one display. The mechanical pod may include ahousing. The housing may further include a flow sensor, a combinedCO2/flow sensor, a CO2 sensor connector (20-pin); and a monitorconnector (7-pin). The CO2/flow sensor may be encoded for automaticpatient category identification. Further, the Sensor may be used forneonatal, pediatric and adult EtCO2 measurements. In an exemplaryembodiment, the sensor may have the dimensions of 1.3×1.7×0.9 in. andmay weigh 18 g. The parameters that may be measured are Carbon dioxide,inspired CO2, partial pressure arterial CO2, mixed expired CO2,end-tidal CO2, and at end-expiration (sidestream).

In embodiments, the device may be a portable bedside monitor that may beused in hospital areas where patients of all ages may be at risk foropioid-induced respiratory depression and arrest. The device may be usedfor all sedation procedures and patient controlled analgesia (PCA).Further, the device may includes superior algorithms that may reducealarms, improve workflow and may provide clinical utility for improvedpatient safety. The device may offer both capnography and pulse oximetryin one monitor. Further, the device may work in a wide range oftemperature environments and measure CO₂ in the presence of variousgases. In an embodiment, the device may not need manual calibration,zeroing, water traps, flushing of monitor between uses, and the like.

In an exemplary embodiment, the device may have a flow rate of 50 ml/minwhich makes the device especially suitable for neonatal sampling. Thedevice may provide an inclusive assessment of patient's ventilatorystatus. Further, the device may be a light-weight monitor which may havea battery life of up to 2 hours which makes it usable for transport. Themonitor may be used for the verification of endotracheal tube ordislodgement of endotracheal tube during transport, for monitoring theeffectiveness of chest compressions during CPR, useful in determiningthe ventilatory status of patients with asthma/COPD, and the like.Thedevice may come with an optional choice of pulse oximetry. The devicemay include a large, color display with a fast, easy to use knobnavigated flat menu structure. In an embodiment, date may be exportedfrom the monitor through its USB port. As mentioned herein, the devicemay be used in all hospital areas and specifically in general patientcare, procedural sedations, in critical care units, in post anesthesiacare unit, and in emergency care.

In embodiments, a portable monitor may employ capnography technology toprovide accurate, continuous monitoring on intubated and non-intubatedpatients. The monitor may be used for neonate to adult patients inhospital settings and emergency transport and other pre-hospitalenvironments. Further, the monitor may be a light-weight monitor thatmay measure EtCO₂ without the need to calibrate for presence of othergases and may work in a wide range of temperature environments. Themonitor may not need manual calibration, zeroing, water traps, flushingof monitor between uses, and the like. In addition, the monitor may havea flow rate of only 50 ml/min which makes the monitor suitable forneonatal sampling.

In embodiments, a monitor may have capnography and pulse oximetry in oneconvenient portable device. The monitor may provide accurate, continuousmonitoring on intubated and non-intubated patients from neonate to adultin hospital and pre-hospital environments, including emergencytransport. Further, the monitor may be a light-weight monitor that maymeasure EtCO₂ without the need to calibrate for presence of other gasesand works in a wide range of temperature environments. The monitor maynot need manual calibration, zeroing, water traps, flushing of monitorbetween uses, and the like. Also, the monitor may have a flow rate ofonly 50 ml/min which makes the monitor suitable for neonatal sampling.

In embodiments, a pocket-sized, fully quantitative capnometer may beprovided. The capnometer may monitor carbon dioxide concentrations andrespiratory rate in patients of all ages. The capnometer may useminiaturized mainstream EtCO2 technology. In an embodiment, thecapnometer may weigh 2.1 oz. The capnometer may not need routinecalibration. In an embodiment, the capnometer may be battery poweredsuch as by two AAA batteries for continuous 8 hour long operation. Thecapnometer may be used for intubation verification, as an indicator forreturn of spontaneous circulation, routine airway management, ventilatortransport, ventilator weaning, and the like.

The capnometer may provide EtCO2 and respiratory rate measurements in afully quantitative numeric value on an LED user interface. Further, thecapnometer may have an optional alarm preset for certain levels ofEtCO2. The capnometer may include two ports. One of the two ports mayconnect to the airway connector and another port may connect to theventilation system. The capnometer may be an effective noninvasiveindicator of cardiac output, CPR effectiveness. Further, the capnometermay also indicate for return of spontaneous circulation duringresuscitation of patients. The capnometer provides accuracy and is alsoeasy to use in all areas of clinical practice.

In embodiments, the present invention may provide a capnography sensor(hereinafter referred as ‘sensor’). The sensor may be a small,lightweight plug-and-play sensor that may be used with a R-seriesdefibrillator. Further, a mainstream sensor may be used for mechanicallyventilated patients and those patients that may be intubated thatrequire intensive monitoring. The capnometer may provide EtCO₂monitoring to verify correct placement of an endotracheal tube, positionof the endotracheal tube, to assess the effectiveness of CPR, and toassess cardiac output in patients with pulse-less electrical activity.The mainstream sensor may be placed on top of an airway adapter that maybe placed directly in the breathing circuit. The airway adapter mayprevent the mainstream sensor from direct contact and contamination withpatient secretions. This may also prevent clogging of sensor or the needfor water traps. The capnometer may also display a printable capnogramon the defibrillator screen for easy identification of abnormalwaveforms.

In embodiments, the oral capnometer 102 may be portable. The portablecapnometer 102 may be useful in evaluating the respiratory condition ofspontaneously breathing patients in hospitals and in in-home care.Further, the portable oral capnometer 102 may be used accurately inspontaneously breathing patients with or without chronic pulmonarydiseases. The oral capnometer 102 may be slipped into a pocket. In anembodiment, the portable capnometer 102 may be powered by two AAAbatteries and may not need calibration. The oral capnometer 102 may havea long battery life.

Further, the oral capnometer 102 may have multiple applications that mayinclude but are not limited to intubation verification, an indicator forreturn of spontaneous circulation, routine airway management, ventilatortransport, and weaning In embodiments, the portable capnometer 102 maybe designed for adults and infants. Further, the portable capnometer 102may include mainstream infrared technology that may enable rapid ‘breathby breath’ measurement of both End tidal C02 and Respiratory Rate. In anembodiment of the present invention, the oral capnometer 102 may includedisposable airway adapters that may be used with or use with CO2 andrespiration monitors.

In embodiments, the oral capnometer 102 may include an indicator 1008,and more specifically, the oral capnometer 102 may include a binaryindicator. The binary indicator may be a visual indicator, an audioindicator, an audio-visual indicator, and the like. The binary indicatormay be used to detect the presence of pulmonary embolism and pulmonaryarterial hypertension in a patient. Further, the binary indicator mayprovide only two results, yes or no. For example, if the patient issuffering from pulmonary embolism, the indicator 1008 may provide anaudio or a visual indication to indicate the presence of the disease. Incase, the disease is not detected the binary indicator may not provideany indication.

It will be evident to a person skilled in the art that the oralcapnometer 102 may indicate the presence as well as absence of adisease. For example, the oral capnometer 102 may include a light sourcethat may produce a red and a green light. The red and the green lightmay provide indication of presence or absence of a disease respectively.In embodiments, the light source may display gradations of color. Forexample, the amount of red may be indicative of how much CO₂ is present,where a pink color may indicate low CO₂ levels and white may indicate noCO₂.

Further, the light source may be a light emitting diode (LED). However,it will be evident to a person skilled in the art that other lightsources may be used instead of LEDs. In other embodiments, the color ofthe indicator light may be associated with the diagnosis.

In embodiments, the oral capnometer 102 may include a device such as alab on chip device (hereinafter referred as device) that may integrateone or several laboratory functions on a single chip. The device may beused as a lung on a chip model. The lung on a chip model may includeliving, breathing human lung on a microchip. The device may be madeusing human lung and blood vessel cells which may predict absorption ofairborne nano particles and mimic the inflammatory response triggered bymicrobial pathogens. Further, the device may be used to test the effectsof environmental toxins, absorption of aerosolized therapeutics, and thesafety and efficacy of new drugs.

In embodiments, pulmonary arterial hypertension (PAH) is a condition inwhich blood pressure in the arteries of the lungs (the pulmonaryarteries) may be abnormally high. PAH may be diagnosed by conductingvarious tests that may include chest x-rays, electrocardiography, andechocardiography on a patient. The test results may provide clues fordiagnosis. However, measurement of blood pressure in a right ventricleand a pulmonary artery may be needed for confirmation of PAH. Further,the tests may provide indications that may be helpful in treatment ofPAH. Such indications may be known as clinical indications.

The clinical indications may enable a physician to prescribe a medicineto a patient. The clinical indications may be a simple and direct way tocommunicate with patients about their medicines. A few extra words maybe added to their prescription to enhance communication. Firstly thereason for the medicine may be explained, for example, Atenolol® ‘toprevent migraine’. In many cases, medicines may have a variety of usesand a precise reason may avoid confusion especially if the medicineinsert leaflets are read. In case of PAH, medicines that may improveblood flow through the lungs may be helpful for patients suffering fromPAH. In embodiments, a cause of sudden PAH may be pulmonary embolism.The oral capnometer 102 may be used to detect the presence of PAH at anearlier stage as would be described later with reference to FIGS. 10-19.

As stated above, the oral capnometer 102 may be used to detect thepresence of PAH at an earlier stage such as described in embodimentsbelow.

FIGS. 10-19 refer to an oral capnometer 1002 that may be used to detectthe presence of PAH at an earlier stage.

In an aspect, the oral capnometer 1002 may include an oral gas capturemember 1004, an end tidal carbon dioxide detection device 1006 and anindicator 1008 as depicted in FIG. 10. The oral gas capture member 1004may collect expired gases from the mouth to determine levels of expiredcarbon dioxide from the mouth of a subject. The end tidal carbon dioxidedetection device 1006 may be attached to the oral gas capture member1004 and may determine levels of the end tidal carbon dioxide at endexpiration from the mouth of a subject. The end tidal carbon dioxidedetection device may include a pressure sensor to determine pressure ofthe end tidal carbon dioxide. The indicator 1008 may be activated whenthe level of the end tidal carbon dioxide falls below a pre-determinedthreshold value.

In an aspect of the invention, the oral gas capture member 1004 maycollect expired gases from the mouth of the patient at pre-determinedregular intervals. In an aspect of the invention, the pressure sensor ofthe end tidal carbon dioxide detection device is a differential pressuresensor. In an aspect of the invention, the end tidal carbon dioxidedetection device may be configured to detect pulmonary arterialhypertension. The end tidal carbon dioxide detection device may be usedto measure partial pressure of expired gases collected in the oral gascapture member 1004. The measured partial pressure may be used fordetection and diagnosis of pulmonary arterial hypertension (PAH).

In an aspect of the invention, the end tidal carbon dioxide detectiondevice may be configured to detect a level of pulmonary arterialhypertension such that the level of pulmonary arterial hypertension maybe monitored over a time interval as will be explained later by the wayof FIGS. 14-17.

In an aspect, a study design may be created for measurement of the endtidal carbon dioxide. In embodiments, a measurement of the end tidalcarbon dioxide (hereafter referred to as EtCO2) may be used todiscriminate pulmonary hypertension (PH) patients with PAH and fromthose with diastolic dysfunction and passive PH. The measurement of theend tidal carbon dioxide may be used to determine the utility of thistechnique in the evaluation and treatment of the PH. Patients with welldefined PH may be tested to determine the predictive value of EtCO2 inthe differential diagnosis of the PH and the change of EtCO2 after atherapeutic change or an escalation. In an aspect, this disclosuredescribes a prospective, single center study designed to investigate thepotential role of EtCO2 in the diagnosis of the PH.

In an aspect, a procedure may be conducted for setting controls (refersto the standard by which experimental observations may be evaluated. Forexample, in many clinical trials, a group of patients may be given anexperimental drug or treatment, while the control group may be given astandard treatment for the illness) and determining population.

In an aspect, all new or returning patients aged ≧18 years of age, whowere evaluated in the Vanderbilt University Center for PulmonaryVascular Disease from August 2009 through March 2010, were eligible forenrollment. In an aspect, the PH may be defined as mean pulmonary arterypressure (mPAP) of 25 mmHg. The PAH may require a pulmonary arteryocclusion pressure (PAOP) of 15 mmHg [30]. A PAOP-pulmonary arterydiastolic (PAd) pressure difference of >11 mm for a diagnosis of PAH[40-43] had been measured. The patients with PVH had no other cause ofPH identified after evaluation and had a PAOP >15 mmHg at rest and hadincreased PAOP >7 mmHg after infusion of 1L normal saline as previouslydescribed [43], or left atrial enlargement on echocardiography andmild-modest elevation in RVSP with no other etiology of PH found afterstandard evaluation and no identified risk factors for PAH. The RHCs(Right Heart Catheterization (RCHs) was performed as previouslydescribed [43]. The exclusion criteria included: ≧5 L/minute nasalcannula oxygen, portopulmonary hypertension (due to cirrhosis associatedhyperventilation), serum bicarbonate >34 mmol/L, pregnancy, knownneuromuscular disease, moderate or severe mitral stenosis, mitral oraortic regurgitation, left ventricular ejection fraction <55% byechocardiography, known hypercarbic respiratory failure, untreated hypo-or hyperthyroidism, hereditary hemorrhagic telangiectasia, uncertaindiagnosis because of incomplete testing, diagnosis of WHO group 3 or 4PH or mixed PH phenotype after thorough evaluation according topublished guidelines [30].

Measurements

In an aspect, a procedure was conducted to measure EtCO2. EtCO2 wasmeasured by a trained tester blinded to diagnosis using the Nellcor NPB75 handheld capnograph (Mallinckrodt:Nellcor, St. Louis, Mo., USA) [44]with the oral gas capture member 1004 of this disclosure. Devicecalibration and oral modification may be performed as previouslydescribed [39]. EtCO2 measurements was recorded for five breaths after apatient or a subject may have rested for at least five minutes and uponcompletion of 6MWT (6 minute walk test) if performed [39]. Demographicdata, results of blood values, 6MWT results, pulmonary function testing,and RHC data was extracted from the medical record. 6MWTs may beperformed according to the American Thoracic Society (ATS) criteria[45].

Healthy Controls—Six Minute Walk Testing

The 6MWT was performed in 13 healthy controls (controls refer to controlindividuals as described above, age mean±SD, 30±7 years; 7 males) withEtCO2 recorded as above.

Determination of the Effects of PAH Treatment on ETCO2

In an aspect, a procedure was conducted for determining the effects ofthe PAH treatment on the EtCO2. The procedure involved measuring theeffects of PAH treatment on EtCO2 among two groups of patients. The twogroups of patients may be referred to as a first group and a secondgroup. The first group of patients initiated treatment with anintravenous or subcutaneous prostaglandin followed by clinicallyprescribed dose uptitration, and the second group of patients receivedan intravenous or subcutaneous prostaglandin wherein a dose increaseof >2 ng/kg/min of epoprostenol or treprostinil may be prescribed fortreatment of worsening symptoms. EtCO2 was measured at a rest positionof the subject or patient prior to and within three months of thetherapeutic change. Poor clinical response was defined by death relatedto PAH or failure to improve one functional class or increase 6MWTdistance by >10% [30, 46].

Statistical Analysis

In an aspect, a statistical analysis was undertaken to analyze theresults obtained from the above procedures. Based on prior publications[43], a 60% positive rate had been assumed for PAH in subjects orpatients for pulmonary vascular disease. In accordance with this rateand a standard deviation (SD) of 3 mmHg in EtCO2 measurements in normalvolunteers, a sample size calculation determined that 102 patients wasrequired to detect a difference in EtCO2 of 2 mmHg between groups with90% power at α-level (significance level) of 0.05. Continuous variableshave been presented herein as mean±SD, unless otherwise noted, and hadbeen analyzed using an unpaired t-test or Wilcoxon Rank Sum testing. Thepatients were enrolled only once, except for patients initiating orincreasing the prostaglandin therapy. The effects of PAH therapy wereanalyzed using paired t-test. Categorical variables have been reportedherein as percentages and had been analyzed using Fisher's exact test.The Receiver Operating Characteristic (ROC) curves with area under thecurve (AUC) were generated for determining sensitivity and specificityof different EtCO2 cutoff levels in discrimination of PAH from patientswithout PAH. All p-values are two-tailed and values 0.05 consideredsignificant. A data analyses has been performed using SPSS for Windowsversion 19.0 (SPSS Inc., Chicago, Ill.) and GraphPad Prism version 5.0c(LaJolla, Calif., USA).

Results

Study Patients

A set of results were obtained from above procedures and statisticalanalysis. In an aspect, the study conducted on patients had also beenaimed at determining demographics of the patients and to study featuresof the patients without PH or severe pulmonary function tests (PTF)abnormalities. The results for this study have been described as followsin Table 4:

TABLE 4 Demography N = 7 Age (years) 52.1 ± 12.0 Number Female (%) 6(86) BMI (kg/m²) 33.6 ± 9.6  Co-morbid conditions Diabetes Mellitus 4Systemic hypertension 5 Hyperlipidemia 3 Pulmonary Function Tests DLCO(%) 75.7 ± 23.9 FEV1 (%) 74.2 ± 12.4 FVC (%) 71.2 ± 13.7 PlasmaBicarbonate (mmol/L) 27.3 ± 2.7  Six Minute Walk Distance (meters) 452.3± 114.9 Hemodynamic Data (5 patients) RAP (mmHg) 4.2 ± 3.6 mPAP (mmHg)17.6 ± 5.2  PAOP or LAP (mmHg) 9.4 ± 2.4 CI (l/m/m²) 2.87 ± 0.9  PVR(Wood units) 1.4 ± 1.1 PAd-PAOP (mmHg) 0.4 ± 1.7

In an aspect, the data in the Table has been presented as mean±SD unlessotherwise noted. Referring to Table 4 as presented herein, BMI refers tobody mass index, DLCO refers to diffusing capacity of carbon monoxide,FEV1 refers to forced expiratory volume in one second, FVC refers toforced vital capacity, RAP refers to right atrial pressure, mPAP refersto mean pulmonary artery pressure, PAOP refers to pulmonary arteryocclusion pressure, LAP refers to left atrial pressure, CI refers tocardiac index, PVR refers to pulmonary vascular resistance, and PAdrefers to diastolic pulmonary artery pressure unless stated otherwise.

Referring to Table 4 and FIG. 11B, demography of the evaluation isillustrated. At step 1103, 280 patients were evaluated for PH over theenrollment period; out of which, at step 1105, 66 new patients and, atstep 1107, 214 were return patients. Out of 280, at step 1109, 168patients consented to enrollment and at step 1111, 112 patients refused.At step 1113, fifty Six (56) patients were excluded due toportopulmonary hypertension (n=5), advanced parenchymal lung disease(n=5), non-group 1 or 2 PH (n=30), miscellaneous causes (HCO3>34 n=5, nofinal diagnosis n=3, incomplete data n=7, uncontrolled hyperthyroidismn=1), wherein n refers to number of patients. One hundred twelve (112)patients were included in the final analysis at step 1115. Eighty four(84) patients were diagnosed with PAH at step 1117, 17 patients with PVHat step 1119, and 11 patients were found to have no PH at step 1121. Inan aspect, out of the 84 patients with PAH, 17 were from functionalclass I, 37 from functional class II, 29 from functional class III, andone from functional class IV. The functional classes referred herein arefrom the PAH diagnosis classification system developed by the WorldHealth Organization (WHO). In an aspect, the causes for the PAH mayinclude idiopathic (n=33), connective tissue disease (n=23), heritablePAH (n=7), congenital heart disease (n=15), and miscellaneous (n=6),wherein n refers to the number of patients. Seven out of eleven patientsin the group were found to have no PH, and only had mild or moderatepulmonary function testing (PTF) abnormalities and normal chest imaging.These patients had been configured to constitute a control cohort (asreferred to in Table 4). The remaining four patients with severelyabnormal parenchyma were not included in the control group. The no PHgroup had a tendency to be obese and frequently had diabetes mellitus,systemic hypertension, and hyperlipidemia. The pulmonary functiontesting did not show severe impairment and 5 patients who had RHC (Rightheart catheterization) data available, the mPAP and PAOP were shown tobe in a normal range. Two patients, who did not have RHC, had normalphysical examination and normal echocardiography.

End Tidal CO2 in PAH and PVH: As stated above, 84 patients had beendiagnosed with PAH and 17 with PVH; these patients had been used formeasurement of the EtCO2. A comparison was drawn between the measuredEtCO2 values from the patients suffering from PAH, PVH and no PH. Thecomparison chart has been shown with reference to Table 5 below andcomparison diagrams are illustrated in FIGS. 11A-11D. The data has beenpresented herein as median with 95% CI.

TABLE 5 Demographic Data in PAH Compared with PVH PAH (n = 84) PVH (n =17) p Value Age (years) 50.5 ± 14.1 63.9 ± 12.2 0.0004 Number Female (%)62 (73.8) 12 (70.6) 0.30 Plasma Bicarbonate (mmol/L) 25.7 ± 3.2  28.1 ±2.4  0.007 Hemodynamic Data (no. 84 PAH, 14 PVH) RAP (mmHg) 7.5 ± 5.911.9 ± 5.8  0.01 mPAP (mmHg) 49.6 ± 15.8 38.6 ± 11.6 0.02 PAOP or LAP(mmHg) 9.0 ± 4.6 19.9 ± 6.9  <0.0001 CI (l/m/m²) 2.6 ± 0.9 3.3 ± 0.70.01 PVR (Wood units) 9.2 ± 5.0 3.4 ± 1.7 0.0001 PAdiastolic-PAOP (mmHg)23.4 ± 11.2 4.4 ± 6.0 <0.0001

In an aspect, the t-test was undertaken for continuous variables,chi-square test for nominal variables, Mann Whitney U test for ordinalvariables. The BMI refers to body mass index, DLCO refers to diffusingcapacity of carbon monoxide, RAP refers to right atrial pressure, mPAPrefers to mean pulmonary artery pressure, PAOP refers to pulmonaryartery occlusion pressure, LAP refers to left atrial pressure, CI refersto cardiac index, PVR refers to pulmonary vascular resistance, and PAdrefers to diastolic pulmonary artery pressure unless stated otherwise.

In an aspect, the PVH patients were found to be older, but had a similarpercentage of females. Plasma bicarbonate was higher in patients withPVH, but values were within the normal range. In patients with availableRHC data, PAOP may confirm PVH or PAH, with a low gradient from the PAdiastolic pressure to the pulmonary artery occlusion pressure (Pad-PAOP)in the PVH group. mPAP and PVR was significantly higher in PAH patientsas compared to those with PVH.

The EtCO2 was compared between PAH, PVH, and no PH group as illustratedin FIG. 11A.

FIG. 11A depicts a mean EtCO2 in PAH, PVH, and no PH patients. MedianEtCO2 was significantly lower in patients with PAH (29.0, 95% CI28.3-30.4 mmHg) as compared with both no PH (38.0, 95% CI 34.4-41.6mmHg) and PVH (41.9, 95% CI 36.6-43.4 mmHg, p<0.0001 PAH vs. bothgroups). A difference in EtCO2 between idiopathic or heritable PAH andconnective tissue disease-associated PAH (data not shown) was notdetected. EtCO2 in patients with no PH was not different from previouslypublished normal mean EtCO2 in healthy controls [39].

An ROC curve was generated evaluating EtCO2 to discriminate between PAH,no PH, and PVH (as depicted in FIG. 12). EtCO2 showed good performancecharacteristics with r² of 0.904. Sensitivities, specificities, andpositive and negative predictive values of EtCO2 in detection of PAH areshown in Table 6.

TABLE 6 Sensitivity and Specificity of a Given Measurement of EtCO2 MeanEtCO2, Positive Negative Positive if ≦ x Predictive Predictive mmHgSensitivity % Specificity % Value % Value % 28 42.9 95.8 97.3 32.4 3060.7 91.7 96.2 40.0 32 75.0 79.2 92.6 47.5 34 86.9 79.2 93.5 63.3 3691.7 70.8 91.6 70.8 38 98.8 62.5 90.2 93.5

FIGS. 13A-13F depict correlation 1300 of EtCO2 with InvasiveHemodynamics.

Correlation of ETCO2 with Invasive Hemodynamics

In an aspect, a study was undertaken to determine the EtCO2 correlationwith invasive hemodynamic measurements differentiating PAH from PVH. 51patients who had RHC within three months of EtCO2 measurement were takenfor this evaluation. In an aspect, EtCO2 was correlated strongly withPAd-PAOP (p=0.0002, FIG. 13C) and also with CI (r=−0.35, p=0.01, FIG.13D), PAOP (r=−0.39, p=0.005, FIG. 13F), and PVR (r=−0.44, p=0.002, FIG.13A). In an aspect, these may be important components in the distinctionbetween PAH and PVH. A correlation of EtCO2 was not observed with meanPA pressure (r=−0.20, p=0.17, FIG. 13E) or right atrial pressure(r=−0.04, p=0.79, FIG. 13B). In the same cohort of patients with RHCdata, there was not a correlation between six minute walk distance andany RHC parameters (data not shown).

Change in ETCO2 vs. Change in 6 Minute Walk Distance

In an aspect, the procedures mentioned above measured a change in EtCO2vs change in 6-minute walk distance.

In some embodiments, the end tidal carbon dioxide detection device maybe configured to detect a level of pulmonary arterial hypertension suchthat the level of pulmonary arterial hypertension can be monitored overa time interval, such as over a treatment interval. This is explainedwith reference to FIGS. 14-17.

In an aspect, the effect of 6MWT on EtCO2 may be compared in healthyvolunteers, PAH and PVH patients in whom both resting and exercise datawere available (n=13 healthy control, 73 PAH, 10 PVH, FIG. 14). In FIG.14, bars denote p=0.0004, other comparisons were not significant. Thedata presented herein is reported with a mean with 95% CI. In healthycontrols, EtCO2 increased after 6MWT [34, 47]. The mean value of EtCO2did not increase in either PAH or PVH after exercise. The EtCO2 did notdecrease in any healthy volunteer with exercise (FIGS. 15A-15C), EtCO2decreased in PAH and PVH patients with exercise. PAH patients, who hadfunctional class III, had decreased EtCO2 after 6MWT as compared topatients with functional class II (p=0.05, as depicted in FIG. 16). Inan aspect, in PAH patients, resting EtCO2 did not correlate with 6MWTdistance (as depicted in FIG. 17). In an aspect, EtCO2 correlated with6MWT distance (r=0.34, p=0.003, n=73) after 6MWT .

In an aspect, the invention can be used to monitor the course of PAHtherapy as mentioned above as the EtCO2 levels change with regard to theadministration of drug therapy. FIG. 18 depicts the change and thephenomena as follows:

Change in ETCO2 with Prostaglandin Therapy

In an aspect, a change in EtCO2 with prostaglandin therapy may bemeasured to monitor the course of treatment of PAH. Fourteen (14) PAHpatients (3 males, age 51±13 years, median follow up 11 months) eitherhad begun prostaglandin therapy (n=7, all epoprostenol) or had anincrease in the dose of prostaglandin to improve symptoms (n=7,6=epoprostenol, 1=treprostinil SQ). The effects of this change intherapy are depicted in FIG. 18. In an aspect, the EtCO2 increased aftertherapy escalation with prostaglandin. FIG. 18 illustrates changes inEtCO2 in the group of patients treated with new or escalating doses ofIV or subcutaneous prostaglandins shown on the left, p=0.03 pairedt-test. The panel at left illustrates change in EtCO2 as a function ofclinical response, p=0.04.

Seven patients were considered to have a poor response (3 patients died,one was referred for transplant, and two neither increased six minutewalk distance by >10% nor improved one functional class). A change inEtCO2, after treatment, differentiated responders from non-responders(p=0.04).

These embodiments described a safe, simple, inexpensive measurement ofEtCO2 at the bedside that may discriminate patients with PAH from thosewith PVH or no PH. EtCO2 may increase with clinical improvementfollowing treatment of PAH, suggesting an improvement in perfusion inpotentially obstructed vessels.

In the present study, resting bedside EtCO2 showed potential for a highnegative predictive value ruling out PAH. In this cohort, the positivepredictive value for EtCO2 38 mmHg was 90.2% and negative predictivevalue for EtCO2 >38 mmHg was 93.5%. If an EtCO2 cutoff of 38 mmHg werechosen in this cohort, we would spare 12/17 diagnostic RHCs for PVH, 3/7for no PH and would have missed 3/84 patients with PAH. EtCO2measurements had strong correlation with hemodynamic measurements forboth the diagnosis of PAH (PAOP, PVR, Pad-PAOP gradient) and alsocorrelated well with CI, an important measure in chronic follow up ofpatients with PAH, but did not correlate with right atrial pressure, amarker of right ventricular failure. These findings fit with themechanism of depression of EtCO2 in PAH, pulmonary arterial obstruction,that would not be affected by right ventricular failure.

Investigators have shown a low EtCO2 in PAH patients and furtherdecrease from baseline with cardiopulmonary exercise testing in PAH [34,38, 47]; findings have been extended using the handheld capnograph 1000of this disclosure and can be further correlated to the EtCO2 withhemodynamic markers of PAH as compared with PVH. The effect of 6MWT onEtCO2 in PAH was examined and it was found that change in EtCO2 washighly variable after exercise. In an aspect, it reflects the variety offunctional classes enrolled in this study (as referred above asfunctional classes developed by WHO) as there may be a trend towarddecrease in EtCO2 after exercise in functional class III patients, butnot in functional classes I or II. In accordance with the variability inchange in EtCO2 after 6MWT, focus has been on resting values forassessment of therapeutic response.

In an aspect, the EtCO2 may increase with clinically successfulprostaglandin treatment for PAH. Six minute walk distance may notcorrelate with any invasive hemodynamic variable, therefore animprovement in EtCO2 may be a more useful surrogate hemodynamic markerin the follow up of PAH patients.

There may be a statistically significant difference in plasmabicarbonate between the patients with PVH and PAH. In an aspect, thismay reflect diuretic use or renal compensation for differences inventilation between the two groups (mentioned above as the first groupand the second group). Arterial PCO₂ might identify a small number oflow EtCO2 values that were false positives for PAH through alveolarhyperventilation.

In one aspect, the invention describes a method 1900. The method 1900may include at step 1902 measuring a carbon dioxide content at endexpiration to obtain an end tidal partial pressure of carbon dioxide inthe subject. This can be done as described above.

At step, 1904, the method 1900 may include diagnosing pulmonary arterialhypertension when the level of the end tidal carbon dioxide measuredfalls below a pre-determined threshold value. This has been describedwith reference to FIGS. 10-18 and Tables 4-6 above.

In an embodiment, an oral capnometer may include an oral gas capturemember that collects expired gases from the mouth, a carbon dioxidemeasuring device attached to the oral gas capture member that determineslevels of end tidal carbon dioxide from the mouth of a subject, and anindicator that is activated when the level of carbon dioxide measured isbelow a pre-determined threshold, wherein the indicator is configured toactivate when the level of the end tidal carbon dioxide falls below athreshold value indicative of a deadspace ventilation disease. Theindicator may be at least one of a visual indicator, an audio indicator,an audio-visual indicator, and a binary indicator. The deadspaceventilation disease may be at least one of pulmonary arterialhypertension and pulmonary embolism. Carbon dioxide levels may bemeasured continuously. The indicator may be configured to deactivatewhen an end tidal carbon dioxide level rises above the pre-determinedthreshold indicating an improvement in the deadspace ventilationdisease.

A method for diagnosis of pulmonary arterial hypertension may includethe steps of measuring a carbon dioxide content at end expiration toobtain an end tidal partial pressure of carbon dioxide in the subjectand diagnosing pulmonary arterial hypertension when the level of the endtidal carbon dioxide measured falls below a threshold value.

In an embodiment and referring to FIG. 10, a system 1000 for determiningwhether or not additional medical tests need to be conducted for thediagnosis of a pulmonary embolism or pulmonary arterial hypertensioncondition in a patient includes a housing 1002 and a carbon dioxideanalyzer 1004 located at least partially within the housing 1002 andadapted to measure the partial pressure of carbon dioxide in a compositegas. A conduit 1008 is adapted to transfer an expiration from thepatient's mouth to the carbon dioxide analyzer 1004. For example, theconduit 1008 may be a tubing attached to an oral adaptor. The system1000 includes at least one of a first processor 1012 and a datatransmitter 1010, the first processor 1012 being located within thehousing 1002 and having a first memory 1014 operably associatedtherewith and the data transmitter 1010 being adapted to transmit datafrom the carbon dioxide analyzer 1004 to a second processor 1022, thesecond processor 1022 being located remotely from the housing 1002 andhaving a second memory 1024 operably associated therewith. A range ofcarbon dioxide partial pressure values may be stored in at least one ofthe first and second memories. An indicator 1018 may be associated withthe first processor 1012 or an indicator 1028 may be associated with thesecond processor 1022. Either indicator 1018, 1028 may be adapted torespond to a signal from at least one of the first and second processors1012, 1022 to provide an output in a human cognizable format. At leastone of the first and second processors 1012, 1022 is adapted to comparea carbon dioxide partial pressure measurement from the carbon dioxideanalyzer 1004 with the range of carbon dioxide partial values and toemit a signal to the indicator 1018, 1028, the signal being indicativeof whether or not additional medical tests need to be conducted for thepatient. Thus, the system 1000 includes a portion within the housingthat receives gas for analysis but then can either transmit the analysisto a remote processor for comparison to a stored value or perform thecomparison on-board.

Referring to FIG. 11, an embodiment of a standalone device 1100 may beused to determine whether or not additional medical tests need to beconducted for the diagnosis of a pulmonary embolism or pulmonaryarterial hypertension condition in a patient. The device 1100 mayinclude a housing 1002, a carbon dioxide analyzer 1004 located at leastpartially within the housing and adapted to measure the partial pressureof carbon dioxide in a composite gas, and a conduit 1008 adapted totransfer an expiration from the patient's mouth to the carbon dioxideanalyzer 1004. A processor 1012 located within the housing 1002 andhaving a memory 1014 operably associated therewith, wherein a range ofcarbon dioxide partial pressure values are stored in the memory 1014. Anindicator 1018 is adapted to respond to a signal from the processor toprovide an output in a human cognizable format. The processor 1012 isadapted to compare a carbon dioxide partial pressure measurement fromthe carbon dioxide analyzer 1004 with the range of carbon dioxidepartial pressure values and to emit a signal to the indicator 1018, thesignal being indicative of whether or not additional medical tests needto be conducted for the patient.

In embodiments and referring to FIG. 12, a two-part system 1200 includesone part that receives expired gas for carbon dioxide analysis andtransmits data using a data transmitter 1010 to a device or computer1020 that contains a processor 1022 and memory 1024. The portion of thesystem 1200 that contains the data transmitter 1010 may not contain aprocessor or memory. The data transmitter 1010 may be a wireless orwired transmitter. In embodiments, a system 1200 for determining whetheror not additional medical tests need to be conducted for the diagnosisof a pulmonary embolism or pulmonary arterial hypertension condition ina patient includes a housing 1002, a carbon dioxide analyzer 1004located at least partially within the housing 1002 and adapted tomeasure the partial pressure of carbon dioxide in a composite gas, aconduit 1008 adapted to transfer an expiration from the patient's mouthto the carbon dioxide analyzer 1004, and a data transmitter 1010 adaptedto transmit data from the carbon dioxide analyzer 1004 to a processor1022, the processor 1022 being located remotely from the housing 1002and having a memory 1024 operably associated therewith. A range ofcarbon dioxide partial pressure values are stored in the memory 1024 andan indicator 1018, 1028 is adapted to respond to a signal from theprocessor 1022 to provide an output in a human cognizable format. Theprocessor 1022 is adapted to compare a carbon dioxide partial pressuremeasurement from the carbon dioxide analyzer 1004 with the range ofcarbon dioxide partial values and to emit a signal to the indicator1018, 1028,the signal being indicative of whether or not additionalmedical tests need to be conducted for the patient. Thus, the system1200 includes a portion within the housing that receives gas foranalysis and then transmits the analysis to a remote processor forcomparison to a stored value.

In an embodiment and referring to FIG. 13, a method for determiningwhether or not additional medical tests need to be conducted for thediagnosis of a pulmonary embolism or pulmonary arterial hypertensioncondition in a patient includes the step of measuring the EtCO2 of eachof a plurality of oral expirations from the patient with a system 1302including a housing, a carbon dioxide analyzer located at leastpartially within the housing and adapted to measure the partial pressureof carbon dioxide in a composite gas, a conduit adapted to transfer anexpiration from the patient's mouth to the carbon dioxide analyzer, atleast one of a first processor and a data transmitter, the firstprocessor being located within the housing and having a first memoryoperably associated therewith and the data transmitter being adapted totransmit data from the carbon dioxide analyzer to a second processor,the second processor being located remotely from the housing and havinga second memory operably associated therewith, a range of carbon dioxidepartial pressure values stored in at least one of the first and secondmemories, and an indicator adapted to respond to a signal from at leastone of the first and second processors to provide an output in a humancognizable format, wherein at least one of the first and secondprocessors is adapted to compare a carbon dioxide partial pressuremeasurement from the carbon dioxide analyzer with the range of carbondioxide partial values and to emit a signal to the indicator, the signalbeing indicative of whether or not additional medical tests need to beconducted for the patient. The method further includes calculating acomposite EtCO2 value for the plurality of oral expirations 1304,comparing the composite EtCO2 value to the range of carbon dioxidepartial pressure values stored in at least one of the first and secondmemories of the system 1308, generating a first signal based upon thecomparison 1310, and transmitting the first signal to the indicator ofthe system 1312.

In an embodiment and referring to FIG. 14, a method for determiningwhether or not additional medical tests need to be conducted for thediagnosis of a pulmonary embolism or pulmonary arterial hypertensioncondition in a patient includes the step of measuring the EtCO2 of eachof a plurality of oral expirations from the patient with a device 1402including a housing, a carbon dioxide analyzer located at leastpartially within the housing and adapted to measure the partial pressureof carbon dioxide in a composite gas, a conduit adapted to transfer anexpiration from the patient's mouth to the carbon dioxide analyzer, afirst processor located within the housing and having a memory operablyassociated therewith, a range of carbon dioxide partial pressure valuesstored in the memory, and an indicator adapted to respond to a signalfrom the processor to provide an output in a human cognizable format,wherein the processor is adapted to compare a carbon dioxide partialpressure measurement from the carbon dioxide analyzer with the range ofcarbon dioxide partial pressure values and to emit a signal to theindicator, the signal being indicative of whether or not additionalmedical tests need to be conducted for the patient. The method furtherincludes calculating a composite EtCO2 value for the plurality of oralexpirations 1404, comparing the composite EtCO2 value to the range ofcarbon dioxide partial pressure values stored in the memory of thedevice 1408, generating a first signal based upon the comparison 1410,and transmitting the first signal to the indicator of the device.

In embodiments and referring to FIG. 15, a method for determiningwhether or not additional medical tests need to be conducted for thediagnosis of a pulmonary embolism or pulmonary arterial hypertensioncondition in a patient may include the step of measuring the EtCO2 ofeach of a plurality of oral expirations from the patient with a system1502 including a housing, a carbon dioxide analyzer located at leastpartially within the housing and adapted to measure the partial pressureof carbon dioxide in a composite gas, a conduit adapted to transfer anexpiration from the patient's mouth to the carbon dioxide analyzer, anda data transmitter adapted to transmit data from the carbon dioxideanalyzer to a processor, the processor being located remotely from thehousing and having a memory operably associated therewith. A range ofcarbon dioxide partial pressure values may be stored in the memory. Anindicator may be adapted to respond to a signal from the processor toprovide an output in a human cognizable format. The processor may beadapted to compare a carbon dioxide partial pressure measurement fromthe carbon dioxide analyzer with the range of carbon dioxide partialvalues and to emit a signal to the indicator, the signal beingindicative of whether or not additional medical tests need to beconducted for the patient. The method further includes calculating acomposite EtCO2 value for the plurality of oral expirations 1504,comparing the composite EtCO2 value to the range of carbon dioxidepartial pressure values stored in the memory of the system 1508,generating a first signal based upon the comparison 1510, andtransmitting the first signal to the indicator of the system 1512.

Thus, in one aspect, each method described above and combinationsthereof may be embodied in computer executable code that, when executingon one or more computing devices, performs the steps thereof. In anotheraspect, the methods may be embodied in systems that perform the stepsthereof, and may be distributed across devices in a number of ways, orall of the functionality may be integrated into a dedicated, standalonedevice or other hardware. In another aspect, the means for performingthe steps associated with the processes described above may include anyof the hardware and/or software described above. All such permutationsand combinations are intended to fall within the scope of the presentdisclosure.

The methods and systems described herein may be deployed in part or inwhole through a machine that executes computer software, program codes,and/or instructions on a processor. The processor may be part of aserver, client, network infrastructure, mobile computing platform,stationary computing platform, or other computing platform. A processormay be any kind of computational or processing device capable ofexecuting program instructions, codes, binary instructions and the like.The processor may be or include a signal processor, digital processor,embedded processor, microprocessor or any variant such as a co-processor(math co-processor, graphic co-processor, communication co-processor andthe like) and the like that may directly or indirectly facilitateexecution of program code or program instructions stored thereon. Inaddition, the processor may enable execution of multiple programs,threads, and codes. The threads may be executed simultaneously toenhance the performance of the processor and to facilitate simultaneousoperations of the application. By way of implementation, methods,program codes, program instructions and the like described herein may beimplemented in one or more thread. The thread may spawn other threadsthat may have assigned priorities associated with them; the processormay execute these threads based on priority or any other order based oninstructions provided in the program code. The processor may includememory that stores methods, codes, instructions and programs asdescribed herein and elsewhere. The processor may access a storagemedium through an interface that may store methods, codes, andinstructions as described herein and elsewhere. The storage mediumassociated with the processor for storing methods, programs, codes,program instructions or other type of instructions capable of beingexecuted by the computing or processing device may include but may notbe limited to one or more of a CD-ROM, DVD, memory, hard disk, flashdrive, RAM, ROM, cache and the like.

A processor may include one or more cores that may enhance speed andperformance of a multiprocessor. In embodiments, the process may be adual core processor, quad core processors, other chip-levelmultiprocessor and the like that combine two or more independent cores(called a die).

The methods and systems described herein may be deployed in part or inwhole through a machine that executes computer software on a server,client, firewall, gateway, hub, router, or other such computer and/ornetworking hardware. The software program may be associated with aserver that may include a file server, print server, domain server,internet server, intranet server and other variants such as secondaryserver, host server, distributed server and the like. The server mayinclude one or more of memories, processors, computer readable media,storage media, ports (physical and virtual), communication devices, andinterfaces capable of accessing other servers, clients, machines, anddevices through a wired or a wireless medium, and the like. The methods,programs or codes as described herein and elsewhere may be executed bythe server. In addition, other devices required for execution of methodsas described in this application may be considered as a part of theinfrastructure associated with the server.

The server may provide an interface to other devices including, withoutlimitation, clients, other servers, printers, database servers, printservers, file servers, communication servers, distributed servers andthe like. Additionally, this coupling and/or connection may facilitateremote execution of program across the network. The networking of someor all of these devices may facilitate parallel processing of a programor method at one or more location without deviating from the scope ofthe invention. In addition, any of the devices attached to the serverthrough an interface may include at least one storage medium capable ofstoring methods, programs, code and/or instructions. A centralrepository may provide program instructions to be executed on differentdevices. In this implementation, the remote repository may act as astorage medium for program code, instructions, and programs.

The software program may be associated with a client that may include afile client, print client, domain client, internet client, intranetclient and other variants such as secondary client, host client,distributed client and the like. The client may include one or more ofmemories, processors, computer readable media, storage media, ports(physical and virtual), communication devices, and interfaces capable ofaccessing other clients, servers, machines, and devices through a wiredor a wireless medium, and the like. The methods, programs or codes asdescribed herein and elsewhere may be executed by the client. Inaddition, other devices required for execution of methods as describedin this application may be considered as a part of the infrastructureassociated with the client.

The client may provide an interface to other devices including, withoutlimitation, servers, other clients, printers, database servers, printservers, file servers, communication servers, distributed servers andthe like. Additionally, this coupling and/or connection may facilitateremote execution of program across the network. The networking of someor all of these devices may facilitate parallel processing of a programor method at one or more location without deviating from the scope ofthe invention. In addition, any of the devices attached to the clientthrough an interface may include at least one storage medium capable ofstoring methods, programs, applications, code and/or instructions. Acentral repository may provide program instructions to be executed ondifferent devices. In this implementation, the remote repository may actas a storage medium for program code, instructions, and programs.

The methods and systems described herein may be deployed in part or inwhole through network infrastructures. The network infrastructure mayinclude elements such as computing devices, servers, routers, hubs,firewalls, clients, personal computers, communication devices, routingdevices and other active and passive devices, modules and/or componentsas known in the art. The computing and/or non-computing device(s)associated with the network infrastructure may include, apart from othercomponents, a storage medium such as flash memory, buffer, stack, RAM,ROM and the like. The processes, methods, program codes, instructionsdescribed herein and elsewhere may be executed by one or more of thenetwork infrastructural elements.

The methods, program codes, and instructions described herein andelsewhere may be implemented on a cellular network having multiplecells. The cellular network may either be frequency division multipleaccess (FDMA) network or code division multiple access (CDMA) network.The cellular network may include mobile devices, cell sites, basestations, repeaters, antennas, towers, and the like. The cell networkmay be a GSM, GPRS, 3G, EVDO, mesh, or other networks types.

The methods, programs codes, and instructions described herein andelsewhere may be implemented on or through mobile devices. The mobiledevices may include navigation devices, cell phones, mobile phones,mobile personal digital assistants, laptops, palmtops, netbooks, pagers,electronic books readers, music players and the like. These devices mayinclude, apart from other components, a storage medium such as a flashmemory, buffer, RAM, ROM and one or more computing devices. Thecomputing devices associated with mobile devices may be enabled toexecute program codes, methods, and instructions stored thereon.Alternatively, the mobile devices may be configured to executeinstructions in collaboration with other devices. The mobile devices maycommunicate with base stations interfaced with servers and configured toexecute program codes. The mobile devices may communicate on a peer topeer network, mesh network, or other communications network. The programcode may be stored on the storage medium associated with the server andexecuted by a computing device embedded within the server. The basestation may include a computing device and a storage medium. The storagedevice may store program codes and instructions executed by thecomputing devices associated with the base station.

The computer software, program codes, and/or instructions may be storedand/or accessed on machine readable media that may include: computercomponents, devices, and recording media that retain digital data usedfor computing for some interval of time; semiconductor storage known asrandom access memory (RAM); mass storage typically for more permanentstorage, such as optical discs, forms of magnetic storage like harddisks, tapes, drums, cards and other types; processor registers, cachememory, volatile memory, non-volatile memory; optical storage such asCD, DVD; removable media such as flash memory (e.g. USB sticks or keys),floppy disks, magnetic tape, paper tape, punch cards, standalone RAMdisks, Zip drives, removable mass storage, off-line, and the like; othercomputer memory such as dynamic memory, static memory, read/writestorage, mutable storage, read only, random access, sequential access,location addressable, file addressable, content addressable, networkattached storage, storage area network, bar codes, magnetic ink, and thelike.

The methods and systems described herein may transform physical and/oror intangible items from one state to another. The methods and systemsdescribed herein may also transform data representing physical and/orintangible items from one state to another.

The elements described and depicted herein, including in flow charts andblock diagrams throughout the figures, imply logical boundaries betweenthe elements. However, according to software or hardware engineeringpractices, the depicted elements and the functions thereof may beimplemented on machines through computer executable media having aprocessor capable of executing program instructions stored thereon as amonolithic software structure, as standalone software modules, or asmodules that employ external routines, code, services, and so forth, orany combination of these, and all such implementations may be within thescope of the present disclosure. Examples of such machines may include,but may not be limited to, personal digital assistants, laptops,personal computers, mobile phones, other handheld computing devices,medical equipment, wired or wireless communication devices, transducers,chips, calculators, satellites, tablet PCs, electronic books, gadgets,electronic devices, devices having artificial intelligence, computingdevices, networking equipments, servers, routers and the like.Furthermore, the elements depicted in the flow chart and block diagramsor any other logical component may be implemented on a machine capableof executing program instructions. Thus, while the foregoing drawingsand descriptions set forth functional aspects of the disclosed systems,no particular arrangement of software for implementing these functionalaspects should be inferred from these descriptions unless explicitlystated or otherwise clear from the context. Similarly, it will beappreciated that the various steps identified and described above may bevaried, and that the order of steps may be adapted to particularapplications of the techniques disclosed herein. All such variations andmodifications are intended to fall within the scope of this disclosure.As such, the depiction and/or description of an order for various stepsshould not be understood to require a particular order of execution forthose steps, unless required by a particular application, or explicitlystated or otherwise clear from the context.

The methods and/or processes described above, and steps thereof, may berealized in hardware, software or any combination of hardware andsoftware suitable for a particular application. The hardware may includea general purpose computer and/or dedicated computing device or specificcomputing device or particular aspect or component of a specificcomputing device. The processes may be realized in one or moremicroprocessors, microcontrollers, embedded microcontrollers,programmable digital signal processors or other programmable device,along with internal and/or external memory. The processes may also, orinstead, be embodied in an application specific integrated circuit, aprogrammable gate array, programmable array logic, or any other deviceor combination of devices that may be configured to process electronicsignals. It will further be appreciated that one or more of theprocesses may be realized as a computer executable code capable of beingexecuted on a machine readable medium.

The computer executable code may be created using a structuredprogramming language such as C, an object oriented programming languagesuch as C++, or any other high-level or low-level programming language(including assembly languages, hardware description languages, anddatabase programming languages and technologies) that may be stored,compiled or interpreted to run on one of the above devices, as well asheterogeneous combinations of processors, processor architectures, orcombinations of different hardware and software, or any other machinecapable of executing program instructions.

While the invention has been disclosed in connection with the preferredembodiments shown and described in detail, various modifications andimprovements thereon will become readily apparent to those skilled inthe art. Accordingly, the spirit and scope of the present invention isnot to be limited by the foregoing examples, but is to be understood inthe broadest sense allowable by law.

All documents referenced herein are hereby incorporated by reference.

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What is claimed is:
 1. A method for determining whether or notadditional medical tests need to be conducted for a diagnosis of apulmonary arterial hypertension condition in a patient, comprising thesteps of: a) measuring end tidal carbon dioxide (EtCO2) of each of aplurality of oral expirations from the patient at rest with a systemcomprising: i) a housing; ii) a carbon dioxide analyzer located at leastpartially within the housing and adapted to measure the partial pressureof carbon dioxide in a composite gas; iii) a conduit adapted to transferan expiration from the patient's mouth to the carbon dioxide analyzer;iv) a data transmitter adapted to transmit data from the carbon dioxideanalyzer to a processor, the processor being located remotely from thehousing and having a memory operably associated therewith; v) a range ofcarbon dioxide partial pressure values stored in the memory; and vi) anindicator adapted to respond to a signal from the processor to providean output in a human cognizable format; b) calculating a composite EtCO2value for the plurality of oral expirations at rest; c) comparing thecomposite EtCO2 value to the range of carbon dioxide partial pressurevalues stored in the memory of the system; d) generating a first signalbased upon the comparison in step (c), the first signal indicative ofwhether or not additional medical tests needs to be conducted for thediagnosis of pulmonary arterial hypertension, wherein a lower range ofthe composite EtCO2 value is indicative of pulmonary arterialhypertension; and e) transmitting the first signal to the indicator ofthe system.
 2. The method of claim 1, wherein each of the plurality oforal expirations from the patient are captured using a tube placed in amouth of the patient.
 3. The method of claim 1, further comprisinginstructing the patient to breathe tidally into a plastic tube insertedinto a mouth of the patient.
 4. The method of claim 1, furthercomprising calibrating the carbon dioxide analyzer for a precision of ±2mm Hg up to 38 mm Hg for a partial pressure of carbon dioxide.
 5. Themethod of claim 1, further comprising calibrating the carbon dioxideanalyzer for a precision of ±0.08% for every 1 mm Hg over 40 mm Hg for apartial pressure of carbon dioxide.
 6. The method of claim 1, furthercomprising administering a 6-minute walking distance test (6MWT) checkto at least one patient for further diagnosis of pulmonary arterialhypertension; and diagnosing pulmonary arterial hypertension when theEtCO2 does not increase after the 6MWT check.
 7. The method of claim 6,further comprising administering the 6MWT after the at least one patienthas received a therapy for the pulmonary arterial hypertension.
 8. Amethod for determining whether or not additional medical tests need tobe conducted for a diagnosis of a pulmonary arterial hypertensioncondition in a patient, comprising the steps of: a) measuring end tidalcarbon dioxide (EtCO2) of each of a plurality of oral expirations fromthe patient at rest with a system comprising: i) a housing; ii) a carbondioxide analyzer located at least partially within the housing andadapted to measure the partial pressure of carbon dioxide in a compositegas; iii) a conduit adapted to transfer an expiration from the patient'smouth to the carbon dioxide analyzer; iv) a data transmitter adapted totransmit data from the carbon dioxide analyzer to a processor, theprocessor being located remotely from the housing and having a memoryoperably associated therewith; v) a range of carbon dioxide partialpressure values stored in the memory; and vi) an indicator adapted torespond to a signal from the processor to provide an output in a humancognizable format; b) calculating a composite EtCO2 value for theplurality of oral expirations at rest; c) comparing the composite EtCO2value to the range of carbon dioxide partial pressure values stored inthe memory of the system; d) generating a first signal based upon thecomparison in step (c), the first signal indicative of whether or notadditional medical tests needs to be conducted for the diagnosis ofpulmonary arterial hypertension, wherein a lower range of the compositeEtCO2 value is indicative of pulmonary arterial hypertension and ahigher range of the composite EtCO2 value is indicative of pulmonaryvenous hypertension; and e) transmitting the first signal to theindicator of the system.
 9. A method for determining whether or notadditional medical tests need to be conducted for a diagnosis of apulmonary arterial hypertension condition in a patient, comprising thesteps of: a) measuring end tidal carbon dioxide (EtCO2) of each of aplurality of oral expirations from the patient at rest with a devicecomprising: i) a housing; ii) a carbon dioxide analyzer located at leastpartially within the housing and adapted to measure the partial pressureof carbon dioxide in a composite gas; iii) a conduit adapted to transferan expiration from the patient's mouth to the carbon dioxide analyzer;iv) a first processor located within the housing and having a memoryoperably associated therewith; v) a range of carbon dioxide partialpressure values stored in the memory; and vi) an indicator adapted torespond to a signal from the processor to provide an output in a humancognizable format; b) calculating a composite EtCO2 value for theplurality of oral expirations at rest c) comparing the composite EtCO2value to the range of carbon dioxide partial pressure values stored inthe memory of the device; d) generating a first signal based upon thecomparison in step (c), the first signal indicative of whether or notadditional medical tests needs to be conducted for the diagnosis ofpulmonary arterial hypertension, wherein a lower range of the compositeEtCO2 value is indicative of pulmonary arterial hypertension; and e)transmitting the first signal to the indicator of the device.
 10. Themethod of claim 9, wherein each of the plurality of oral expirationsfrom the patient are captured using a tube placed in a mouth of thepatient.
 11. The method of claim 9, further comprising instructing thepatient to breathe tidally into a plastic tube inserted into a mouth ofthe patient.
 12. The method of claim 9, further comprising calibratingthe carbon dioxide analyzer for a precision of ±2 mm Hg up to 38 mm Hgfor a partial pressure of carbon dioxide.
 13. The method of claim 9,further comprising calibrating the carbon dioxide analyzer for aprecision of ±0.08% for every 1 mm Hg over 40 mm Hg for a partialpressure of carbon dioxide.
 14. The method of claim 9, furthercomprising administering a 6-minute walking distance test (6MWT) checkto at least one patient for further diagnosis of pulmonary arterialhypertension; and diagnosing pulmonary arterial hypertension when theEtCO2 does not increase after the 6MWT check.
 15. the method of claim14, further comprising administering the 6MWT after the at least onepatient has received a therapy for the pulmonary arterial hypertension.16. A method for determining whether or not additional medical testsneed to be conducted for a diagnosis of a pulmonary arterialhypertension condition in a patient, comprising the steps of: a)measuring end tidal carbon dioxide (EtCO2) of each of a plurality oforal expirations from the patient at rest with a device comprising: i) ahousing; ii) a carbon dioxide analyzer located at least partially withinthe housing and adapted to measure the partial pressure of carbondioxide in a composite gas; iii) a conduit adapted to transfer anexpiration from the patient's mouth to the carbon dioxide analyzer; iv)a first processor located within the housing and having a memoryoperably associated therewith; v)a range of carbon dioxide partialpressure values stored in the memory; and vi) an indicator adapted torespond to a signal from the processor to provide an output in a humancognizable format; b) calculating a composite EtCO2 value for theplurality of oral expirations at rest; c) comparing the composite EtCO2value to the range of carbon dioxide partial pressure values stored inthe memory of the device; d) generating a first signal based upon thecomparison in step (c), the first signal indicative of whether or notadditional medical tests needs to be conducted for the diagnosis ofpulmonary arterial hypertension, wherein a lower range of the compositeEtCO2 value is indicative of pulmonary arterial hypertension and ahigher range of the composite EtCO2 value is indicative of pulmonaryvenous hypertension; and e) transmitting the first signal to theindicator of the device.